5t37: Difference between revisions
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==crystal structure of mPGES-1 bound to inhibitor== | ==crystal structure of mPGES-1 bound to inhibitor== | ||
<StructureSection load='5t37' size='340' side='right' caption='[[5t37]], [[Resolution|resolution]] 1.76Å' scene=''> | <StructureSection load='5t37' size='340' side='right'caption='[[5t37]], [[Resolution|resolution]] 1.76Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5t37]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T37 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T37 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5t37]] is a 1 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=5T37 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T37 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=758:2-CHLORO-5-{[(2,2-DIMETHYLPROPANOYL)AMINO]METHYL}-N-(1H-IMIDAZOL-2-YL)BENZAMIDE'>758</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=758:2-CHLORO-5-{[(2,2-DIMETHYLPROPANOYL)AMINO]METHYL}-N-(1H-IMIDAZOL-2-YL)BENZAMIDE'>758</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTGES, MGST1L1, MPGES1, PGES, PIG12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-E_synthase Prostaglandin-E synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.3 5.3.99.3] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-E_synthase Prostaglandin-E synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.3 5.3.99.3] </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=5t37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t37 OCA], [http://pdbe.org/5t37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t37 RCSB], [http://www.ebi.ac.uk/pdbsum/5t37 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t37 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=5t37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t37 OCA], [http://pdbe.org/5t37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t37 RCSB], [http://www.ebi.ac.uk/pdbsum/5t37 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t37 ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5t37" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5t37" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Prostaglandin E synthase|Prostaglandin E synthase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Prostaglandin-E synthase]] | [[Category: Prostaglandin-E synthase]] | ||
[[Category: Antonysamy, S]] | [[Category: Antonysamy, S]] | ||
Revision as of 12:22, 4 December 2019
crystal structure of mPGES-1 bound to inhibitorcrystal structure of mPGES-1 bound to inhibitor
Structural highlights
Function[PTGES_HUMAN] Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).[1] Publication Abstract from PubMedWe describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000x, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours. Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1.,Partridge KM, Antonysamy S, Bhattachar SN, Chandrasekhar S, Fisher MJ, Fretland A, Gooding K, Harvey A, Hughes NE, Kuklish SL, Luz JG, Manninen PR, McGee JE, Mudra DR, Navarro A, Norman BH, Quimby SJ, Schiffler MA, Sloan AV, Warshawsky AM, Weller JM, York JS, Yu XP Bioorg Med Chem Lett. 2017 Mar 15;27(6):1478-1483. doi:, 10.1016/j.bmcl.2016.11.011. Epub 2016 Nov 7. PMID:28190634[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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