4dhy - Revision history

OCA at 14:35, 14 March 2024

2024-03-14T14:35:50Z

←Older revision		Revision as of 14:35, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dhy]] is a 1 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=4DHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DHY FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dhy]] is a 1 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=4DHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DHY FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</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]] 2.38Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [https://pdbe.org/4dhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [https://www.ebi.ac.uk/pdbsum/4dhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dhy 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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [https://pdbe.org/4dhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [https://www.ebi.ac.uk/pdbsum/4dhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dhy ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[https://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[https://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>	+	[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[https://omim.org/entry/125851 125851]; also shortened MODY-2. MODY 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:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[https://omim.org/entry/602485 602485]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.	+	[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and ones that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKA) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion (GSIS), but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK/glucose complex in a wide-open conformation. To assess conformations of GK in solution, we also carried out small angle X-ray scattering (SAXS) experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared to wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKA with reduced hypoglycemic risk.	+
-		+
-	Insights into the mechanism of glucokinase activation: observation of multiple distinct protein conformations.,Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X J Biol Chem. 2012 Feb 1. PMID:22298776<ref>PMID:22298776</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4dhy" style="background-color:#fffaf0;"></div>~~	+

	==See Also==		==See Also==

OCA at 08:19, 21 September 2022

2022-09-21T08:19:05Z

←Older revision		Revision as of 08:19, 21 September 2022
Line 1:		Line 1:

	==Crystal structure of human glucokinase in complex with glucose and activator==		==Crystal structure of human glucokinase in complex with glucose and activator==
-	<StructureSection load='4dhy' size='340' side='right' caption='[[4dhy]], [[Resolution\|resolution]] 2.38Å' scene=''>	+	<StructureSection load='4dhy' size='340' side='right'caption='[[4dhy]], [[Resolution\|resolution]] 2.38Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4dhy]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DHY OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4DHY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4dhy]] is a 1 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=4DHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DHY FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3s41\|3s41]], [[3vev\|3vev]], [[3ve6\|3ve6]], [[3vf6\|3vf6]], [[4dch\|4dch]]</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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [https://pdbe.org/4dhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [https://www.ebi.ac.uk/pdbsum/4dhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dhy ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GCK ([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/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [~~http~~://pdbe.org/4dhy PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4dhy PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4dhy ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[~~http~~://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[~~http~~://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>	+	[[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[https://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[https://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.	+	[[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 22:

	==See Also==		==See Also==
-	*[[Hexokinase\|Hexokinase]]	+	*[[Hexokinase 3D structures\|Hexokinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Glucokinase~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Human~~]]	+	[[Category: Large Structures]]
-	[[Category: Liu, S]]	+	[[Category: Liu S]]
-	~~[[Category: Diabetes mellitus]]~~	+
-	~~[[Category: Disease mutation]]~~	+
-	~~[[Category: Glycolysis]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase activator complex~~]]	+

OCA at 17:10, 11 August 2016

2016-08-11T17:10:54Z

←Older revision		Revision as of 17:10, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of human glucokinase in complex with glucose and activator==		==Crystal structure of human glucokinase in complex with glucose and activator==
	<StructureSection load='4dhy' size='340' side='right' caption='[[4dhy]], [[Resolution\|resolution]] 2.38Å' scene=''>		<StructureSection load='4dhy' size='340' side='right' caption='[[4dhy]], [[Resolution\|resolution]] 2.38Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4dhy]] is a 1 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=4DHY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DHY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4dhy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DHY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DHY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3s41\|3s41]], [[3vev\|3vev]], [[3ve6\|3ve6]], [[3vf6\|3vf6]], [[4dch\|4dch]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3s41\|3s41]], [[3vev\|3vev]], [[3ve6\|3ve6]], [[3vf6\|3vf6]], [[4dch\|4dch]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GCK ([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">GCK ([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/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [http://www.ebi.ac.uk/pdbsum/4dhy 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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [http://pdbe.org/4dhy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [http://www.ebi.ac.uk/pdbsum/4dhy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dhy ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 4dhy" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 29:		Line 31:
	</StructureSection>		</StructureSection>
	[[Category: Glucokinase]]		[[Category: Glucokinase]]
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Liu, S]]		[[Category: Liu, S]]
	[[Category: Diabetes mellitus]]		[[Category: Diabetes mellitus]]

OCA at 14:01, 4 January 2015

2015-01-04T14:01:48Z

←Older revision		Revision as of 14:01, 4 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4dhy\| PDB=4dhy \| SCENE= }}~~	+	==Crystal structure of human glucokinase in complex with glucose and activator==
-	===Crystal structure of human glucokinase in complex with glucose and activator===	+	<StructureSection load='4dhy' size='340' side='right' caption='[[4dhy]], [[Resolution\|resolution]] 2.38Å' scene=''>
-	{~~{ABSTRACT_PUBMED_22298776}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4dhy]] is a 1 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=4DHY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DHY FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=S41:N,N-DIMETHYL-5-({2-METHYL-6-[(5-METHYLPYRAZIN-2-YL)CARBAMOYL]-1-BENZOFURAN-4-YL}OXY)PYRIMIDINE-2-CARBOXAMIDE'>S41</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3s41\|3s41]], [[3vev\|3vev]], [[3ve6\|3ve6]], [[3vf6\|3vf6]], [[4dch\|4dch]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GCK ([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/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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=4dhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dhy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dhy RCSB], [http://www.ebi.ac.uk/pdbsum/4dhy PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[http://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[http://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and ones that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKA) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion (GSIS), but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK/glucose complex in a wide-open conformation. To assess conformations of GK in solution, we also carried out small angle X-ray scattering (SAXS) experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared to wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKA with reduced hypoglycemic risk.

-	~~==Disease==~~	+	Insights into the mechanism of glucokinase activation: observation of multiple distinct protein conformations.,Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X J Biol Chem. 2012 Feb 1. PMID:22298776<ref>PMID:22298776</ref>
-	~~[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are~~ the ~~cause~~ of ~~maturity-onset diabetes~~ of ~~the young type 2 (MODY2) [MIM:[http://omim~~.~~org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref><ref>PMID:1464666</ref><ref>PMID:1303265</ref><ref>PMID:8495817</ref><ref>PMID:8325892</ref><ref>PMID:8446612</ref><ref>PMID:8168652</ref><ref>PMID:9049484</ref><ref>PMID:10694920</ref><ref>PMID:9662401</ref><ref>PMID:10588527</ref><ref>PMID:11106831</ref><ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[http://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:~~9435328~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~/~~/www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has~~ a ~~high Km for glucose, and so it is effective only when glucose is abundant. The role~~ of ~~GCK is to provide G6P for~~ the ~~synthesis of glycogen~~. ~~Pancreatic glucokinase plays an important role in modulating insulin secretion~~. ~~Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant~~ of ~~hepatic glucose usage~~.	+	</div>
-		+
-	~~==About this Structure==~~	+
-	~~[[4dhy]] is a 1 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=4DHY OCA].~~	+

	==See Also==		==See Also==
	*[[Hexokinase\|Hexokinase]]		*[[Hexokinase\|Hexokinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:022298776</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Glucokinase]]		[[Category: Glucokinase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Liu, S.]]	+	[[Category: Liu, S]]
	[[Category: Diabetes mellitus]]		[[Category: Diabetes mellitus]]
	[[Category: Disease mutation]]		[[Category: Disease mutation]]

OCA at 02:32, 25 March 2013

2013-03-25T02:32:05Z

←Older revision		Revision as of 02:32, 25 March 2013
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-	[[Image:4dhy.png\|left\|200px]]
-
	{{STRUCTURE_4dhy\| PDB=4dhy \| SCENE= }}		{{STRUCTURE_4dhy\| PDB=4dhy \| SCENE= }}
-
	===Crystal structure of human glucokinase in complex with glucose and activator===		===Crystal structure of human glucokinase in complex with glucose and activator===
		+	{{ABSTRACT_PUBMED_22298776}}

-	~~{{ABSTRACT_PUBMED_22298776}}~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[http://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY 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:1502186</ref><ref>PMID:1464666</ref><ref>PMID:1303265</ref><ref>PMID:8495817</ref><ref>PMID:8325892</ref><ref>PMID:8446612</ref><ref>PMID:8168652</ref><ref>PMID:9049484</ref><ref>PMID:10694920</ref><ref>PMID:9662401</ref><ref>PMID:10588527</ref><ref>PMID:11106831</ref><ref>PMID:11372010</ref> Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[http://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:022298776</ref><references group="xtra"/>	+	<ref group="xtra">PMID:022298776</ref><references group="xtra"/><references/>
	[[Category: Glucokinase]]		[[Category: Glucokinase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]

OCA at 12:39, 20 October 2012

2012-10-20T12:39:23Z

←Older revision		Revision as of 12:39, 20 October 2012
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	[[Image:4dhy.png\|left\|200px]]		[[Image:4dhy.png\|left\|200px]]

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	{{STRUCTURE_4dhy\| PDB=4dhy \| SCENE= }}		{{STRUCTURE_4dhy\| PDB=4dhy \| SCENE= }}

	===Crystal structure of human glucokinase in complex with glucose and activator===		===Crystal structure of human glucokinase in complex with glucose and activator===

-
-	<!--
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	{{ABSTRACT_PUBMED_22298776}}		{{ABSTRACT_PUBMED_22298776}}

	==About this Structure==		==About this Structure==
	[[4dhy]] is a 1 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=4DHY OCA].		[[4dhy]] is a 1 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=4DHY OCA].
		+
		+	==See Also==
		+	*[[Hexokinase\|Hexokinase]]

	==Reference==		==Reference==

OCA at 06:21, 11 April 2012

2012-04-11T06:21:28Z

←Older revision		Revision as of 06:21, 11 April 2012
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-	[[Image:4dhy.~~jpg~~\|left\|200px]]	+	[[Image:4dhy.png\|left\|200px]]

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	===Crystal structure of human glucokinase in complex with glucose and activator===		===Crystal structure of human glucokinase in complex with glucose and activator===

		+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_22298776}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 22298776 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_22298776}}

	==About this Structure==		==About this Structure==
	[[4dhy]] is a 1 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=4DHY OCA].		[[4dhy]] is a 1 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=4DHY OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:022298776</ref><references group="xtra"/>
	[[Category: Glucokinase]]		[[Category: Glucokinase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]

OCA: Protected "4dhy" [edit=sysop:move=sysop]

2012-02-08T06:47:43Z

Protected "4dhy" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:47, 8 February 2012