5qii
From Proteopedia
(Difference between revisions)
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<StructureSection load='5qii' size='340' side='right' caption='[[5qii]], [[Resolution|resolution]] 2.45Å' scene=''> | <StructureSection load='5qii' size='340' side='right' caption='[[5qii]], [[Resolution|resolution]] 2.45Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5qii]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QII OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5QII FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5qii]] is a 4 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=5QII OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5QII FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HJG:2-{3-[1-(4-chlorophenyl)cyclopropyl][1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol'>HJG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HJG:2-{3-[1-(4-chlorophenyl)cyclopropyl][1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol'>HJG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD11B1, HSD11, HSD11L, SDR26C1 ([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/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] </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=5qii FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qii OCA], [http://pdbe.org/5qii PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5qii RCSB], [http://www.ebi.ac.uk/pdbsum/5qii PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5qii 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=5qii FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qii OCA], [http://pdbe.org/5qii PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5qii RCSB], [http://www.ebi.ac.uk/pdbsum/5qii PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5qii ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity). | [[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11beta-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials. | ||
| + | |||
| + | Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD-1).,Li J, Kennedy LJ, Walker SJ, Wang H, Li JJ, Hong Z, O'Connor SP, Ye XY, Chen S, Wu S, Yoon DS, Nayeem A, Camac DM, Ramamurthy V, Morin PE, Sheriff S, Wang M, Harper TW, Golla R, Seethala R, Harrity T, Ponticiello RP, Morgan NN, Taylor JR, Zebo R, Maxwell B, Moulin F, Gordon DA, Robl JA ACS Med Chem Lett. 2018 Nov 13;9(12):1170-1174. doi:, 10.1021/acsmedchemlett.8b00307. eCollection 2018 Dec 13. PMID:30613321<ref>PMID:30613321</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5qii" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: 11-beta-hydroxysteroid dehydrogenase]] | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | ||
| + | [[Category: Human]] | ||
[[Category: Sheriff, S]] | [[Category: Sheriff, S]] | ||
[[Category: 11b-hsd1]] | [[Category: 11b-hsd1]] | ||
Revision as of 12:23, 16 January 2019
CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-(3-(1-(4-CHLOROPHENYL)CYCLOPROPYL) -[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-8-YL)PROPAN-2-OL
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