4dch: Difference between revisions

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 ==Insights into Glucokinase Activation Mechanism: Observation of Multiple Distinct Protein Conformations==
-<StructureSection load='4dch' size='340' side='right' caption='[[4dch]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
+<StructureSection load='4dch' size='340' side='right'caption='[[4dch]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4dch]] 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=4DCH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4dch]] 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=4DCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4DC:(2R)-3-CYCLOPENTYL-2-[4-(METHYLSULFONYL)PHENYL]-N-(1,3-THIAZOL-2-YL)PROPANAMIDE'>4DC</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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]] 1.79&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4DC:(2R)-3-CYCLOPENTYL-2-[4-(METHYLSULFONYL)PHENYL]-N-(1,3-THIAZOL-2-YL)PROPANAMIDE'>4DC</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4dch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dch OCA], [https://pdbe.org/4dch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dch RCSB], [https://www.ebi.ac.uk/pdbsum/4dch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dch ProSAT]</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=4dch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dch OCA], [http://pdbe.org/4dch PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dch RCSB], [http://www.ebi.ac.uk/pdbsum/4dch PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dch ProSAT]</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>
+[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 ==
-[[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;">
-== 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>
+==See Also==
+*[[Hexokinase 3D structures|Hexokinase 3D structures]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4dch" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Glucokinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
+[[Category: Large Structures]]
-[[Category: Feng, J]]
+[[Category: Feng J]]
-[[Category: Garcia, E]]
+[[Category: Garcia E]]
-[[Category: Greasley, S E]]
+[[Category: Greasley SE]]
-[[Category: Hickey, M]]
+[[Category: Hickey M]]
-[[Category: Gk beta cell]]
-[[Category: Kinase]]
-[[Category: Open conformation]]
-[[Category: Small molecule]]
-[[Category: Transferase]]