3w12 - Revision history

OCA at 12:45, 8 November 2023

OCA — Wed, 08 Nov 2023 12:45:15 GMT

←Older revision		Revision as of 12:45, 8 November 2023
Line 3:		Line 3:
	<StructureSection load='3w12' size='340' side='right'caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>		<StructureSection load='3w12' size='340' side='right'caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~] and [https://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W12 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W12 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=BMA:BETA~~-~~D-MANNOSE'>BMA</scene>~~, ~~<scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 4.301Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=~~PR9~~:D-~~PROLINAMIDE~~'>~~PR9~~</scene><~~/td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>
-	~~<tr id~~='~~related'><td class~~=~~"sblockLbl"><b>[[Related_structure\|Related~~:~~]]</b></td><td class="sblockDat"><div style='overflow: auto; max~~-~~height: 3em;~~'>~~[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]~~</~~div~~><~~/td></tr>~~	+
-	~~<tr id~~='~~gene'><td class~~=~~"sblockLbl"><b>[[Gene\|Gene~~:~~]]</b~~></td><~~td class="sblockDat">INSR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+
-	~~<tr id~~='~~activity'><td class~~=~~"sblockLbl"><b>Activity~~:~~</b></td><td class="sblockDat"><span class='plainlinks~~'>~~[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1]~~ </~~span~~></td></tr>	+
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [https://pdbe.org/3w12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [https://www.ebi.ac.uk/pdbsum/3w12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w12 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [https://pdbe.org/3w12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [https://www.ebi.ac.uk/pdbsum/3w12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w12 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[https://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[https://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[https://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[https://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[https://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[https://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[https://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[https://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[https://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>	+	[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[https://omim.org/entry/262190 262190]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[https://omim.org/entry/246200 246200]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[https://omim.org/entry/609968 609968]. Familial hyperinsulinemic hypoglycemia [MIM:[https://omim.org/entry/256450 256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[https://omim.org/entry/610549 610549]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.	+	[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 32:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Lk3 transgenic mice]]~~	+	[[Category: Mus musculus]]
-	~~[[Category: Receptor protein-tyrosine kinase~~]]	+	[[Category: Brzozowsk AM]]
-	[[Category: Brzozowsk~~, A M~~]]	+	[[Category: Lawrence MC]]
-	[[Category: Lawrence~~, M C~~]]	+	[[Category: Smith BJ]]
-	[[Category: Smith~~, B J]]~~	+
-	~~[[Category: Cell surface receptor/immune system]]~~	+
-	~~[[Category: Ct peptide]]~~	+
-	~~[[Category: Hormone receptor-hormone-immune system complex]]~~	+
-	~~[[Category: Insulin]]~~	+
-	~~[[Category: Insulin receptor]]~~	+
-	~~[[Category: Ir ectodomain~~]]	+

OCA at 05:17, 3 August 2022

OCA — Wed, 03 Aug 2022 05:17:40 GMT

←Older revision		Revision as of 05:17, 3 August 2022
Line 1:		Line 1:

	==Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7==		==Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7==
-	<StructureSection load='3w12' size='340' side='right' caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>	+	<StructureSection load='3w12' size='340' side='right'caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human] and [~~http~~://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3W12 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human] and [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W12 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INSR ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INSR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [~~http~~://pdbe.org/3w12 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3w12 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3w12 ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [https://pdbe.org/3w12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [https://www.ebi.ac.uk/pdbsum/3w12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w12 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[~~http~~://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[~~http~~://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[~~http~~://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[~~http~~://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[~~http~~://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[~~http~~://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[~~http~~://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[~~http~~://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[~~http~~://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[~~http~~://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[~~http~~://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>	+	[[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[https://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[https://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[https://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[https://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[https://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[https://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[https://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[https://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[https://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[~~http~~://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.	+	[[https://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[https://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 26:

	==See Also==		==See Also==
-	*[[3D structures ~~of monoclonal antibody~~\|3D structures ~~of monoclonal antibody~~]]	+	*[[Insulin receptor 3D structures\|Insulin receptor 3D structures]]
		+	*[[Monoclonal Antibodies 3D structures\|Monoclonal Antibodies 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 32:		Line 33:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Lk3 transgenic mice]]		[[Category: Lk3 transgenic mice]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]

OCA at 13:31, 11 August 2016

OCA — Thu, 11 Aug 2016 13:31:35 GMT

←Older revision		Revision as of 13:31, 11 August 2016
Line 1:		Line 1:
		+
	==Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7==		==Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7==
	<StructureSection load='3w12' size='340' side='right' caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>		<StructureSection load='3w12' size='340' side='right' caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~] and [http://en.wikipedia.org/wiki/~~Mus_musculus Mus musculus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W12 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W12 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INSR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INSR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [http://www.ebi.ac.uk/pdbsum/3w12 PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [http://pdbe.org/3w12 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [http://www.ebi.ac.uk/pdbsum/3w12 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3w12 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 22:		Line 23:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 3w12" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
-	*[[~~Monoclonal Antibody~~\|~~Monoclonal Antibody~~]]	+	*[[3D structures of monoclonal antibody\|3D structures of monoclonal antibody]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
-	[[Category: ~~Mus musculus~~]]	+	[[Category: Lk3 transgenic mice]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Brzozowsk, A M]]		[[Category: Brzozowsk, A M]]

OCA at 14:27, 5 January 2015

OCA — Mon, 05 Jan 2015 14:27:08 GMT

←Older revision		Revision as of 14:27, 5 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}~~	+	==Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7==
-	===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===	+	<StructureSection load='3w12' size='340' side='right' caption='[[3w12]], [[Resolution\|resolution]] 4.30Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23302862}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W12 FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PR9:D-PROLINAMIDE'>PR9</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2dtg\|2dtg]], [[3loh\|3loh]], [[2wrw\|2wrw]], [[3w11\|3w11]], [[3w13\|3w13]], [[3w14\|3w14]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INSR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w12 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w12 RCSB], [http://www.ebi.ac.uk/pdbsum/3w12 PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>		[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>
-		+	== Function ==
-	==Function==	+
	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.		[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alphaCT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.

-	~~==About this Structure==~~	+	How insulin engages its primary binding site on the insulin receptor.,Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Zakova L, Kletvikova E, Jiracek J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC Nature. 2013 Jan 10;493(7431):241-5. doi: 10.1038/nature11781. PMID:23302862<ref>PMID:23302862</ref>
-	~~[[3w12]] is a 6 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens] and [http~~:~~//en~~.~~wikipedia~~.~~org~~/~~wiki/Mus_musculus Mus musculus]~~. ~~Full crystallographic information is available from [http~~://~~oca~~.~~weizmann~~.ac.il/~~oca-bin/ocashort?id=3W12 OCA].~~	+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

	==See Also==		==See Also==
	*[[Monoclonal Antibody\|Monoclonal Antibody]]		*[[Monoclonal Antibody\|Monoclonal Antibody]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:023302862</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mus musculus]]		[[Category: Mus musculus]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Brzozowsk, A M.]]	+	[[Category: Brzozowsk, A M]]
-	[[Category: Lawrence, M C.]]	+	[[Category: Lawrence, M C]]
-	[[Category: Smith, B J.]]	+	[[Category: Smith, B J]]
	[[Category: Cell surface receptor/immune system]]		[[Category: Cell surface receptor/immune system]]
	[[Category: Ct peptide]]		[[Category: Ct peptide]]

OCA at 09:01, 4 September 2013

OCA — Wed, 04 Sep 2013 09:01:45 GMT

←Older revision		Revision as of 09:01, 4 September 2013
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	{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}		{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}
	===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===		===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===
		+	{{ABSTRACT_PUBMED_23302862}}

	==Disease==		==Disease==
-	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref><ref>PMID:2365819</ref><ref>PMID:8314008</ref><ref>PMID:10443650</ref><ref>PMID:12023989</ref><ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref><ref>PMID:12023989</ref><ref>PMID:2834824</ref><ref>PMID:2479553</ref><ref>PMID:1607067</ref><ref>PMID:1730625</ref><ref>PMID:8326490</ref><ref>PMID:8419945</ref><ref>PMID:8188715</ref><ref>PMID:7815442</ref><ref>PMID:7538143</ref><ref>PMID:8636294</ref><ref>PMID:9299395</ref><ref>PMID:9249867</ref><ref>PMID:9703342</ref><ref>PMID:12538626</ref><ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref><ref>PMID:1470163</ref><ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref><ref>PMID:2196279</ref><ref>PMID:4019786</ref><ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref><ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref><ref>PMID:18162506</ref><ref>PMID:20226046</ref>	+	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>

	==Function==		==Function==
-	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref><ref>PMID:8452530</ref><ref>PMID:8276809</ref><ref>PMID:9428692</ref><ref>PMID:10207053</ref><ref>PMID:12138094</ref><ref>PMID:16314505</ref><ref>PMID:16831875</ref> [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.	+	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.

	==About this Structure==		==About this Structure==
	[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA].		[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA].
		+
		+	==See Also==
		+	*[[Monoclonal Antibody\|Monoclonal Antibody]]

	==Reference==		==Reference==
-	<references group="xtra"/><references/>	+	<ref group="xtra">PMID:023302862</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mus musculus]]		[[Category: Mus musculus]]

OCA at 21:52, 24 March 2013

OCA — Sun, 24 Mar 2013 21:52:19 GMT

←Older revision		Revision as of 21:52, 24 March 2013
Line 1:		Line 1:
-	[[Image:3w12.png\|left\|200px]]
-
	{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}		{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}
-
	===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===		===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===

		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref><ref>PMID:2365819</ref><ref>PMID:8314008</ref><ref>PMID:10443650</ref><ref>PMID:12023989</ref><ref>PMID:17201797</ref> Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref><ref>PMID:12023989</ref><ref>PMID:2834824</ref><ref>PMID:2479553</ref><ref>PMID:1607067</ref><ref>PMID:1730625</ref><ref>PMID:8326490</ref><ref>PMID:8419945</ref><ref>PMID:8188715</ref><ref>PMID:7815442</ref><ref>PMID:7538143</ref><ref>PMID:8636294</ref><ref>PMID:9299395</ref><ref>PMID:9249867</ref><ref>PMID:9703342</ref><ref>PMID:12538626</ref><ref>PMID:12970295</ref> Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref><ref>PMID:1470163</ref><ref>PMID:7657032</ref> Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref> Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref><ref>PMID:2196279</ref><ref>PMID:4019786</ref><ref>PMID:1601997</ref> Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref> Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref><ref>PMID:18162506</ref> Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref><ref>PMID:18162506</ref><ref>PMID:20226046</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref><ref>PMID:8452530</ref><ref>PMID:8276809</ref><ref>PMID:9428692</ref><ref>PMID:10207053</ref><ref>PMID:12138094</ref><ref>PMID:16314505</ref><ref>PMID:16831875</ref> [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.

	==About this Structure==		==About this Structure==
	[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA].		[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA].
		+
		+	==Reference==
		+	<references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mus musculus]]		[[Category: Mus musculus]]

OCA at 09:18, 16 January 2013

OCA — Wed, 16 Jan 2013 09:18:30 GMT

←Older revision		Revision as of 09:18, 16 January 2013
Line 1:		Line 1:
-	[[Image:3w12.~~jpg~~\|left\|200px]]	+	[[Image:3w12.png\|left\|200px]]

	{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}		{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}

OCA at 08:20, 9 January 2013

OCA — Wed, 09 Jan 2013 08:20:29 GMT

←Older revision		Revision as of 08:20, 9 January 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3w12.jpg\|left\|200px]]

-	~~The entry~~ 3w12 ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_3w12\| PDB=3w12 \| SCENE= }}

-	~~Authors: Lawrence~~, ~~M.C., Smith, B.J., Brzozowsk, A.M.~~	+	===Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7===

-	~~Description: Insulin receptor ectodomain construct comprising domains L1-CR in complex~~ with ~~high-affinity insulin analogue~~ [D-~~PRO-B26~~]-~~DTI-NH2~~, ~~alpha-CT~~ peptide~~(704~~-~~719) and FAB 83~~-7	+
		+	==About this Structure==
		+	[[3w12]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W12 OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Mus musculus]]
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Brzozowsk, A M.]]
		+	[[Category: Lawrence, M C.]]
		+	[[Category: Smith, B J.]]
		+	[[Category: Cell surface receptor/immune system]]
		+	[[Category: Ct peptide]]
		+	[[Category: Hormone receptor-hormone-immune system complex]]
		+	[[Category: Insulin]]
		+	[[Category: Insulin receptor]]
		+	[[Category: Ir ectodomain]]

OCA at 08:35, 2 January 2013

OCA — Wed, 02 Jan 2013 08:35:51 GMT

←Older revision		Revision as of 08:35, 2 January 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3w12 is ON HOLD	+	The entry 3w12 is ON HOLD until Paper Publication

	Authors: Lawrence, M.C., Smith, B.J., Brzozowsk, A.M.		Authors: Lawrence, M.C., Smith, B.J., Brzozowsk, A.M.

-	Description: Insulin receptor ectodomain domains L1-CR in complex with high-affinity insulin analogue ~~and~~ CT peptide	+	Description: Insulin receptor ectodomain construct comprising domains L1-CR in complex with high-affinity insulin analogue [D-PRO-B26]-DTI-NH2, alpha-CT peptide(704-719) and FAB 83-7

OCA: Protected "3w12" [edit=sysop:move=sysop]

OCA — Wed, 14 Nov 2012 06:05:38 GMT

Protected "3w12" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:05, 14 November 2012