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==Human GKRP complexed to AMG-1694 [(2R)-1,1,1-trifluoro-2-{4-[(2S)-2-{[(3S)-3-methylmorpholin-4-yl]methyl}-4-(thiophen-2-ylsulfonyl)piperazin-1-yl]phenyl}propan-2-ol] and sorbitol-6-phosphate==
==Human GKRP complexed to AMG-1694 [(2R)-1,1,1-trifluoro-2-{4-[(2S)-2-{[(3S)-3-methylmorpholin-4-yl]methyl}-4-(thiophen-2-ylsulfonyl)piperazin-1-yl]phenyl}propan-2-ol] and sorbitol-6-phosphate==
<StructureSection load='4ly9' size='340' side='right' caption='[[4ly9]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
<StructureSection load='4ly9' size='340' side='right'caption='[[4ly9]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ly9]] 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=4LY9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LY9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ly9]] 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=4LY9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LY9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1YY:(2R)-1,1,1-TRIFLUORO-2-{4-[(2S)-2-{[(3S)-3-METHYLMORPHOLIN-4-YL]METHYL}-4-(THIOPHEN-2-YLSULFONYL)PIPERAZIN-1-YL]PHENYL}PROPAN-2-OL'>1YY</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]] 2.35&#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=1YY:(2R)-1,1,1-TRIFLUORO-2-{4-[(2S)-2-{[(3S)-3-METHYLMORPHOLIN-4-YL]METHYL}-4-(THIOPHEN-2-YLSULFONYL)PIPERAZIN-1-YL]PHENYL}PROPAN-2-OL'>1YY</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=4ly9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ly9 OCA], [http://pdbe.org/4ly9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ly9 RCSB], [http://www.ebi.ac.uk/pdbsum/4ly9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ly9 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=4ly9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ly9 OCA], [https://pdbe.org/4ly9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ly9 RCSB], [https://www.ebi.ac.uk/pdbsum/4ly9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ly9 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 ==
Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.
 
Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors.,Lloyd DJ, St Jean DJ Jr, Kurzeja RJ, Wahl RC, Michelsen K, Cupples R, Chen M, Wu J, Sivits G, Helmering J, Komorowski R, Ashton KS, Pennington LD, Fotsch C, Vazir M, Chen K, Chmait S, Zhang J, Liu L, Norman MH, Andrews KL, Bartberger MD, Van G, Galbreath EJ, Vonderfecht SL, Wang M, Jordan SR, Veniant MM, Hale C Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13. PMID:24226772<ref>PMID:24226772</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ly9" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Glucokinase Regulatory Protein|Glucokinase Regulatory Protein]]
*[[Glucokinase Regulatory Protein|Glucokinase Regulatory Protein]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Jordan, S R]]
[[Category: Large Structures]]
[[Category: Carbohydrate binding protein]]
[[Category: Jordan SR]]
[[Category: Disruptor ligand complex]]
[[Category: Gkrp binds to gk]]
[[Category: Liver]]
[[Category: Regulatory protein]]
[[Category: Sis domain]]

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