4iju

From Proteopedia

Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with (1S,4S)-4-[8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridin-3-yl]bicyclo[2.2.1]heptan-1-ol

Structural highlights

4iju is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.35Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DHI1_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).

Function

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).

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD-1). ACS Med Chem Lett. 2014 May 22;5(7):803-8. doi: 10.1021/ml500144h. eCollection, 2014 Jul 10. PMID:25050169 doi:http://dx.doi.org/10.1021/ml500144h