2hr7

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{{STRUCTURE_2hr7| PDB=2hr7 | SCENE= }}
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==Insulin receptor (domains 1-3)==
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===Insulin receptor (domains 1-3)===
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<StructureSection load='2hr7' size='340' side='right' caption='[[2hr7]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
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{{ABSTRACT_PUBMED_16894147}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2hr7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HR7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2HR7 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene><br>
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<tr><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>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hr7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hr7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2hr7 RCSB], [http://www.ebi.ac.uk/pdbsum/2hr7 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[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.
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== Function ==
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[[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hr/2hr7_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF1R) are homologous multidomain proteins that bind insulin and IGF with differing specificity. Here we report the crystal structure of the first three domains (L1-CR-L2) of human IR at 2.3 A resolution and compare it with the previously determined structure of the corresponding fragment of IGF1R. The most important differences seen between the two receptors are in the two regions governing ligand specificity. The first is at the corner of the ligand-binding surface of the L1 domain, where the side chain of F39 in IR forms part of the ligand binding surface involving the second (central) beta-sheet. This is very different to the location of its counterpart in IGF1R, S35, which is not involved in ligand binding. The second major difference is in the sixth module of the CR domain, where IR contains a larger loop that protrudes further into the ligand-binding pocket. This module, which governs IGF1-binding specificity, shows negligible sequence identity, significantly more alpha-helix, an additional disulfide bond, and opposite electrostatic potential compared to that of the IGF1R.
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==Disease==
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The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity.,Lou M, Garrett TP, McKern NM, Hoyne PA, Epa VC, Bentley JD, Lovrecz GO, Cosgrove LJ, Frenkel MJ, Ward CW Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12429-34. Epub 2006 Aug 7. PMID:16894147<ref>PMID:16894147</ref>
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[[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.
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[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>
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</div>
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==About this Structure==
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[[2hr7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HR7 OCA].
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==See Also==
==See Also==
*[[Insulin receptor|Insulin receptor]]
*[[Insulin receptor|Insulin receptor]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:016894147</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 08:36, 30 September 2014

Insulin receptor (domains 1-3)

2hr7, resolution 2.32Å

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