4olh: Difference between revisions
New page: '''Unreleased structure''' The entry 4olh is ON HOLD Authors: Jordan, S. R., Chmait, S. Description: Human GKRP Bound to AMG5106 and Sorbitol-6-Phosphate |
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==Human GKRP Bound to AMG5106 and Sorbitol-6-Phosphate== | |||
<StructureSection load='4olh' size='340' side='right'caption='[[4olh]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4olh]] 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=4OLH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OLH 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]] 2.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2TO:2-(2-{4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]PIPERAZIN-1-YL}-3,3-BIPYRIDIN-5-YL)-1,1,1,3,3,3-HEXAFLUOROPROPAN-2-OL'>2TO</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=4olh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olh OCA], [https://pdbe.org/4olh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4olh RCSB], [https://www.ebi.ac.uk/pdbsum/4olh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4olh 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 == | |||
Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 muM and EC50 = 0.205 muM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose. | |||
Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket.,Hong FT, Norman MH, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Fotsch C, Jordan SR, Lloyd DJ, Sivits G, Tadesse S, Hale C, St Jean DJ Jr J Med Chem. 2014 Jul 8. PMID:25001129<ref>PMID:25001129</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4olh" 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 20:16, 20 September 2023
Human GKRP Bound to AMG5106 and Sorbitol-6-PhosphateHuman GKRP Bound to AMG5106 and Sorbitol-6-Phosphate
Structural highlights
FunctionGCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme. Publication Abstract from PubMedStructure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 muM and EC50 = 0.205 muM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose. Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket.,Hong FT, Norman MH, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Fotsch C, Jordan SR, Lloyd DJ, Sivits G, Tadesse S, Hale C, St Jean DJ Jr J Med Chem. 2014 Jul 8. PMID:25001129[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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