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4ijw

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==Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-cyclopropyl[1,2,4]triazolo[4,3-a]pyridine==
==Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-cyclopropyl[1,2,4]triazolo[4,3-a]pyridine==
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<StructureSection load='4ijw' size='340' side='right' caption='[[4ijw]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
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<StructureSection load='4ijw' size='340' side='right'caption='[[4ijw]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4ijw]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IJW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IJW FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4ijw]] 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=4IJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IJW FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1EQ:3-[1-(4-CHLOROPHENYL)CYCLOPROPYL]-8-CYCLOPROPYL[1,2,4]TRIAZOLO[4,3-A]PYRIDINE'>1EQ</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene><br>
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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]] 2.35&#8491;</td></tr>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4iju|4iju]], [[4ijv|4ijv]]</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=1EQ:3-[1-(4-CHLOROPHENYL)CYCLOPROPYL]-8-CYCLOPROPYL[1,2,4]TRIAZOLO[4,3-A]PYRIDINE'>1EQ</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr><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=4ijw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ijw OCA], [https://pdbe.org/4ijw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ijw RCSB], [https://www.ebi.ac.uk/pdbsum/4ijw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ijw ProSAT]</span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ijw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ijw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ijw RCSB], [http://www.ebi.ac.uk/pdbsum/4ijw PDBsum]</span></td></tr>
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</table>
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<table>
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== 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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Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11beta-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.
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Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD-1).,Li J, Kennedy LJ, Wang H, Li JJ, Walker SJ, Hong Z, O'Connor SP, Nayeem A, Camac DM, Morin PE, Sheriff S, Wang M, Harper T, Golla R, Seethala R, Harrity T, Ponticiello RP, Morgan NN, Taylor JR, Zebo R, Gordon DA, Robl JA ACS Med Chem Lett. 2014 May 22;5(7):803-8. doi: 10.1021/ml500144h. eCollection, 2014 Jul 10. PMID:25050169<ref>PMID:25050169</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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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: Sheriff, S.]]
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[[Category: Large Structures]]
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[[Category: 11b-hsd1]]
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[[Category: Sheriff S]]
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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 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-cyclopropyl[1,2,4]triazolo[4,3-a]pyridine

PDB ID 4ijw

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