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| | <StructureSection load='4olh' size='340' side='right'caption='[[4olh]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='4olh' size='340' side='right'caption='[[4olh]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4olh]] 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=4OLH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OLH FirstGlance]. <br> | + | <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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ohk|4ohk]], [[4ohm|4ohm]], [[4oho|4oho]], [[4ohp|4ohp]], [[4op1|4op1]], [[4op2|4op2]], [[4op3|4op3]]</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='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='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> |
| - | <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=4olh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olh OCA], [http://pdbe.org/4olh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4olh RCSB], [http://www.ebi.ac.uk/pdbsum/4olh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4olh 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chmait, S]] | + | [[Category: Chmait S]] |
| - | [[Category: Jordan, S R]] | + | [[Category: Jordan SR]] |
| - | [[Category: Binds to and inhibits glucokinase]]
| + | |
| - | [[Category: Carbohydrate binding protein]]
| + | |
| - | [[Category: Glucokinase]]
| + | |
| - | [[Category: Liver]]
| + | |
| - | [[Category: Regulatory protein]]
| + | |
| - | [[Category: Sis domain]]
| + | |
| Structural highlights
4olh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.4Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket. J Med Chem. 2014 Jul 8. PMID:25001129 doi:http://dx.doi.org/10.1021/jm5001979
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