6cir

Human Cytochrome P450 17A1 in complex with inhibitor: abiraterone C6 oxime

spinqualitylabelsall models 6cir, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cir is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3NQ, HEM Gene: CYP17A1, CYP17, S17AH (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [CP17A_HUMAN] Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency;46,XY disorder of sex development due to isolated 17, 20 lyase deficiency. The disease is caused by mutations affecting the gene represented in this entry. Function [CP17A_HUMAN] Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty. Publication Abstract from PubMed Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects. Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2.,Fehl C, Vogt CD, Yadav R, Li K, Scott EE, Aube J J Med Chem. 2018 May 24. doi: 10.1021/acs.jmedchem.8b00419. PMID:29792703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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