4GL5

Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)

4GL5 の概要

• エントリーDOI: 10.2210/pdb4gl5/pdb
• 関連するPDBエントリー: 3EQM 3S79 3S7S 4GL7
• 分子名称: Cytochrome P450 19A1, PROTOPORPHYRIN IX CONTAINING FE, (6alpha,8alpha)-6-(but-2-yn-1-yloxy)androsta-1,4-diene-3,17-dione (3 entities in total)
• 機能のキーワード: oxidoreductase, estrogen synthetase, cytochrome p450 reductase, er membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Peripheral membrane protein: P11511
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58923.82

構造登録者

Ghosh, D. (登録日: 2012-08-13, 公開日: 2012-09-12, 最終更新日: 2024-02-28)

主引用文献

Ghosh, D.,Lo, J.,Morton, D.,Valette, D.,Xi, J.,Griswold, J.,Hubbell, S.,Egbuta, C.,Jiang, W.,An, J.,Davies, H.M.
Novel aromatase inhibitors by structure-guided design.
J.Med.Chem., 55:8464-8476, 2012

PubMed Abstract: Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.

PubMed: 22951074
DOI: 10.1021/jm300930n

実験手法

X-RAY DIFFRACTION (3.48 Å)