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5qii

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==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==
==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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<StructureSection load='5qii' size='340' side='right' caption='[[5qii]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
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<StructureSection load='5qii' size='340' side='right'caption='[[5qii]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<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>
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<table><tr><td colspan='2'>[[5qii]] is a 4 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=5QII OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QII FirstGlance]. <br>
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</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5qii FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qii OCA], [https://pdbe.org/5qii PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qii RCSB], [https://www.ebi.ac.uk/pdbsum/5qii PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qii ProSAT]</span></td></tr>
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<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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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[http://omim.org/entry/604931 604931]]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).
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[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[https://omim.org/entry/604931 604931]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).
== Function ==
== Function ==
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[[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).
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[https://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).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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 &gt;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.
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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>
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==See Also==
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5qii" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 11-beta-hydroxysteroid dehydrogenase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Sheriff, S]]
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[[Category: Sheriff S]]
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[[Category: 11b-hsd1]]
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[[Category: Dehydrogenase]]
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[[Category: Hydroxysteroid]]
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[[Category: Inhibitor]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Sdr]]
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Current revision

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

PDB ID 5qii

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