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==Human GKRP bound to AMG-6861 and Sorbitol-6-phosphate==
==Human GKRP bound to AMG-6861 and Sorbitol-6-phosphate==
<StructureSection load='4msu' size='340' side='right' caption='[[4msu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='4msu' size='340' side='right'caption='[[4msu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4msu]] is a 2 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=4MSU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MSU FirstGlance]. <br>
<table><tr><td colspan='2'>[[4msu]] is a 2 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=4MSU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MSU FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2EU:1,1,1,3,3,3-HEXAFLUORO-2-{4-[4-(THIOPHEN-2-YLSULFONYL)PIPERAZIN-1-YL]PHENYL}PROPAN-2-OL'>2EU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.5&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCKR ([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=2EU:1,1,1,3,3,3-HEXAFLUORO-2-{4-[4-(THIOPHEN-2-YLSULFONYL)PIPERAZIN-1-YL]PHENYL}PROPAN-2-OL'>2EU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4msu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4msu OCA], [http://pdbe.org/4msu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4msu RCSB], [http://www.ebi.ac.uk/pdbsum/4msu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4msu 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=4msu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4msu OCA], [https://pdbe.org/4msu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4msu RCSB], [https://www.ebi.ac.uk/pdbsum/4msu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4msu ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/GCKR_HUMAN GCKR_HUMAN]] Inhibits glucokinase by forming an inactive complex with this enzyme.
[https://www.uniprot.org/uniprot/GCKR_HUMAN GCKR_HUMAN] Inhibits glucokinase by forming an inactive complex with this enzyme.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.


Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept.,Ashton KS, Andrews KL, Bryan MC, Chen J, Chen K, Chen M, Chmait S, Croghan M, Cupples R, Fotsch C, Helmering J, Jordan SR, Kurzeja RJ, Michelsen K, Pennington LD, Poon SF, Sivits G, Van G, Vonderfecht SL, Wahl RC, Zhang J, Lloyd DJ, Hale C, St Jean DJ Jr J Med Chem. 2014 Jan 23;57(2):309-24. doi: 10.1021/jm4016735. Epub 2014 Jan 9. PMID:24405172<ref>PMID:24405172</ref>
==See Also==
 
*[[Glucokinase Regulatory Protein|Glucokinase Regulatory Protein]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4msu" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Andrews, K L]]
[[Category: Large Structures]]
[[Category: Ashton, K S]]
[[Category: Andrews KL]]
[[Category: Bryan, M C]]
[[Category: Ashton KS]]
[[Category: Chen, J]]
[[Category: Bryan MC]]
[[Category: Chen, K]]
[[Category: Chen J]]
[[Category: Chen, M]]
[[Category: Chen K]]
[[Category: Chmait, S]]
[[Category: Chen M]]
[[Category: Croghan, M]]
[[Category: Chmait S]]
[[Category: Cupples, R]]
[[Category: Croghan M]]
[[Category: Fotsch, C]]
[[Category: Cupples R]]
[[Category: Hale, C]]
[[Category: Fotsch C]]
[[Category: Helmering, J]]
[[Category: Hale C]]
[[Category: Jean, D J.St]]
[[Category: Helmering J]]
[[Category: Jordan, S R]]
[[Category: Jordan SR]]
[[Category: Kurzeja, R J]]
[[Category: Kurzeja RJ]]
[[Category: Lloyd, D J]]
[[Category: Lloyd DJ]]
[[Category: Michelsen, K]]
[[Category: Michelsen K]]
[[Category: Pennington, L D]]
[[Category: Pennington LD]]
[[Category: Poon, S F]]
[[Category: Poon SF]]
[[Category: Sivits, G]]
[[Category: Sivits G]]
[[Category: Van, G]]
[[Category: St Jean DJ]]
[[Category: Vonderfecht, S L]]
[[Category: Van G]]
[[Category: Wahl, R C]]
[[Category: Vonderfecht SL]]
[[Category: Zhang, J]]
[[Category: Wahl RC]]
[[Category: Glucokinase]]
[[Category: Zhang J]]
[[Category: Phospho-fructose]]
[[Category: Regulatory protein]]
[[Category: Sis domain]]
[[Category: Sugar binding protein]]

Latest revision as of 12:28, 1 March 2024

Human GKRP bound to AMG-6861 and Sorbitol-6-phosphate

4msu, resolution 2.50Å

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