4ijv: Difference between revisions
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==Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridine== | |||
<StructureSection load='4ijv' size='340' side='right'caption='[[4ijv]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ijv]] 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=4IJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IJV FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1EN:3-[1-(4-CHLOROPHENYL)CYCLOPROPYL]-8-(2-FLUOROPHENOXY)[1,2,4]TRIAZOLO[4,3-A]PYRIDINE'>1EN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=4ijv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ijv OCA], [https://pdbe.org/4ijv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ijv RCSB], [https://www.ebi.ac.uk/pdbsum/4ijv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ijv ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[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 == | |||
[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). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4ijv" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Sheriff S]] | |||
Latest revision as of 18:25, 20 September 2023
Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridineCrystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridine
Structural highlights
DiseaseDHI1_HUMAN Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM: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). FunctionDHI1_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). Publication Abstract from PubMedSmall 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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