5t7r - Revision history

OCA at 15:37, 6 March 2024

OCA — Wed, 06 Mar 2024 15:37:50 GMT

←Older revision		Revision as of 15:37, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='5t7r' size='340' side='right'caption='[[5t7r]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='5t7r' size='340' side='right'caption='[[5t7r]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5t7r]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7R OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5T7R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5t7r]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T7R FirstGlance]. <br>
-	</td></tr><tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non~~-~~Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</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]] 1.55Å</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=5t7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t7r OCA], [~~http~~://pdbe.org/5t7r PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5t7r RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5t7r PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5t7r ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene></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=5t7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t7r OCA], [https://pdbe.org/5t7r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t7r RCSB], [https://www.ebi.ac.uk/pdbsum/5t7r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t7r ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[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/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/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/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 ==~~	+
-	The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Calpha-Calpha distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Calpha-Calpha distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.	+
-		+
-	Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity.,van Lierop B, Ong SC, Belgi A, Delaine C, Andrikopoulos S, Haworth NL, Menting JG, Lawrence MC, Robinson AJ, Forbes BE Sci Rep. 2017 Dec 8;7(1):17239. doi: 10.1038/s41598-017-16876-3. PMID:29222417<ref>PMID:29222417</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5t7r" style="background-color:#fffaf0;"></div>~~	+

	==See Also==		==See Also==
-	*[[~~Molecular Playground/~~Insulin\|~~Molecular Playground/~~Insulin]]	+	*[[Insulin 3D Structures\|Insulin 3D Structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Forbes~~, B E~~]]	+	[[Category: Forbes BE]]
-	[[Category: Lawrence~~, M C~~]]	+	[[Category: Lawrence MC]]
-	[[Category: Menting~~, J G~~]]	+	[[Category: Menting JG]]
-	[[Category: Robinson~~, A J]]~~	+	[[Category: Robinson AJ]]
-	~~[[Category: Hormone]]~~	+
-	~~[[Category: Insulin dicarba bond~~]]	+

OCA at 06:22, 19 June 2019

OCA — Wed, 19 Jun 2019 06:22:49 GMT

←Older revision		Revision as of 06:22, 19 June 2019
Line 1:		Line 1:

	==A6-A11 trans-dicarba human insulin==		==A6-A11 trans-dicarba human insulin==
-	<StructureSection load='5t7r' size='340' side='right' caption='[[5t7r]], [[Resolution\|resolution]] 1.55Å' scene=''>	+	<StructureSection load='5t7r' size='340' side='right'caption='[[5t7r]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5t7r]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T7R FirstGlance]. <br>		<table><tr><td colspan='2'>[[5t7r]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T7R FirstGlance]. <br>
Line 11:		Line 11:
	== Function ==		== Function ==
	[[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/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 ==
		+	The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Calpha-Calpha distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Calpha-Calpha distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.
		+
		+	Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity.,van Lierop B, Ong SC, Belgi A, Delaine C, Andrikopoulos S, Haworth NL, Menting JG, Lawrence MC, Robinson AJ, Forbes BE Sci Rep. 2017 Dec 8;7(1):17239. doi: 10.1038/s41598-017-16876-3. PMID:29222417<ref>PMID:29222417</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5t7r" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Molecular Playground/Insulin\|Molecular Playground/Insulin]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Forbes, B E]]		[[Category: Forbes, B E]]
	[[Category: Lawrence, M C]]		[[Category: Lawrence, M C]]

OCA at 07:12, 6 December 2017

OCA — Wed, 06 Dec 2017 07:12:41 GMT

←Older revision		Revision as of 07:12, 6 December 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5t7r is ~~ON HOLD~~ ~~until Paper Publication~~	+	==A6-A11 trans-dicarba human insulin==
-		+	<StructureSection load='5t7r' size='340' side='right' caption='[[5t7r]], [[Resolution\|resolution]] 1.55Å' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5t7r]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T7R FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=5t7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t7r OCA], [http://pdbe.org/5t7r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t7r RCSB], [http://www.ebi.ac.uk/pdbsum/5t7r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t7r ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[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/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.
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Forbes, B E]]
		+	[[Category: Lawrence, M C]]
		+	[[Category: Menting, J G]]
		+	[[Category: Robinson, A J]]
		+	[[Category: Hormone]]
		+	[[Category: Insulin dicarba bond]]

OCA at 16:47, 26 October 2016

OCA — Wed, 26 Oct 2016 16:47:56 GMT

←Older revision		Revision as of 16:47, 26 October 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5t7r is ON HOLD	+	The entry 5t7r is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "5t7r" [edit=sysop:move=sysop]

OCA — Wed, 14 Sep 2016 14:06:28 GMT

Protected "5t7r" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:06, 14 September 2016

OCA: New page: '''Unreleased structure''' The entry 5t7r is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 14 Sep 2016 14:06:26 GMT

New page: '''Unreleased structure''' The entry 5t7r is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5t7r is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]