6CHI

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

6CHI の概要

• エントリーDOI: 10.2210/pdb6chi/pdb
• 分子名称: Steroid 17-alpha-hydroxylase/17,20 lyase, PROTOPORPHYRIN IX CONTAINING FE, 3-hydroxy-17-(3-pyridyl)-androst-5,16-dien-6-amide, ... (4 entities in total)
• 機能のキーワード: cytochrome p450, p450, cyp17a1, p450c17, p450 17a1, monooxygenase, 17a-hydroxylase, heme protein, cytochrome p450 oxidoreductase, membrane, microsome, endoplasmic reticulum, oxidoreductase-oxidoreductase inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 226996.65

構造登録者

Scott, E.E. (登録日: 2018-02-22, 公開日: 2018-06-06, 最終更新日: 2023-10-04)

主引用文献

Fehl, C.,Vogt, C.D.,Yadav, R.,Li, K.,Scott, E.E.,Aube, J.
Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2.
J. Med. Chem., 61:4946-4960, 2018

PubMed Abstract: 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.

PubMed: 29792703
DOI: 10.1021/acs.jmedchem.8b00419

実験手法

X-RAY DIFFRACTION (2.698 Å)