4op2: Difference between revisions
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==GKRP bound to AMG-0471 and Sorbitol-6-Phosphate== | |||
<StructureSection load='4op2' size='340' side='right'caption='[[4op2]], [[Resolution|resolution]] 2.24Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4op2]] 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=4OP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OP2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.24Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2UX:(2S)-2-{4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]BIPHENYL-4-YL}-1,1,1-TRIFLUOROPROPAN-2-OL'>2UX</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'>[https://proteopedia.org/fgij/fg.htm?mol=4op2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4op2 OCA], [https://pdbe.org/4op2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4op2 RCSB], [https://www.ebi.ac.uk/pdbsum/4op2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4op2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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 == | |||
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK. | |||
Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.,Tamayo NA, Norman MH, Bartberger MD, Hong FT, Bo Y, Liu L, Nishimura N, Yang KC, Tadesse S, Fotsch C, Chen J, Chmait S, Cupples R, Hale C, Jordan SR, Lloyd DJ, Sivits G, Van G, St Jean DJ Jr J Med Chem. 2015 Jun 11;58(11):4462-82. doi: 10.1021/jm5018175. Epub 2015 Jun 1. PMID:25914941<ref>PMID:25914941</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4op2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glucokinase Regulatory Protein|Glucokinase Regulatory Protein]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chmait S]] | |||
[[Category: Jordan SR]] | |||
Latest revision as of 20:17, 20 September 2023
GKRP bound to AMG-0471 and Sorbitol-6-PhosphateGKRP bound to AMG-0471 and Sorbitol-6-Phosphate
Structural highlights
FunctionGCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme. Publication Abstract from PubMedThe glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK. Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.,Tamayo NA, Norman MH, Bartberger MD, Hong FT, Bo Y, Liu L, Nishimura N, Yang KC, Tadesse S, Fotsch C, Chen J, Chmait S, Cupples R, Hale C, Jordan SR, Lloyd DJ, Sivits G, Van G, St Jean DJ Jr J Med Chem. 2015 Jun 11;58(11):4462-82. doi: 10.1021/jm5018175. Epub 2015 Jun 1. PMID:25914941[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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