View source for 4mlh


==Human Glucokinase in Complex with a Novel Amino Thiazole Allosteric Activator==
<StructureSection load='4mlh' size='340' side='right'caption='[[4mlh]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4mlh]] 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=4MLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MLH 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=VO2:3-(BENZYLOXY)-5-METHYL-N-(4-METHYL-1,3-THIAZOL-2-YL)PYRIDIN-2-AMINE'>VO2</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=4mlh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mlh OCA], [https://pdbe.org/4mlh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mlh RCSB], [https://www.ebi.ac.uk/pdbsum/4mlh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mlh ProSAT]</span></td></tr>
</table>
== 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> 
== 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.

Identification of a New Class of Glucokinase Activators through Structure-Based Design.,Hinklin RJ, Boyd SA, Chicarelli MJ, Condroski KR, Dewolf WE Jr, Lee PA, Lee W, Singh A, Thomas L, Voegtli WC, Williams L, Aicher TD J Med Chem. 2013 Sep 25. PMID:24015910<ref>PMID:24015910</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4mlh" style="background-color:#fffaf0;"></div>

==See Also==
*[[Hexokinase 3D structures|Hexokinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Voegtli WC]]