9BVB

Crystal structure of human CYP3A4 in complex with SJYHJ-075

これはPDB形式変換不可エントリーです。

9BVB の概要

• エントリーDOI: 10.2210/pdb9bvb/pdb
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, 2-(2-chlorophenyl)-N-[(2P)-2-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]acetamide (3 entities in total)
• 機能のキーワード: cytochrome p450 3a4, cyp3a4, cyp3a4-selective inhibitor, drug metabolizing enzyme, 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: 1
• 化学式量合計: 56590.89

構造登録者

Jingheng, W.,Nithianantham, S.,Miller, D.J.,Chen, T. (登録日: 2024-05-20, 公開日: 2025-04-16, 最終更新日: 2025-04-23)

主引用文献

Wang, J.,Nithianantham, S.,Chai, S.C.,Jung, Y.H.,Yang, L.,Ong, H.W.,Li, Y.,Zhang, Y.,Miller, D.J.,Chen, T.
Decoding the selective chemical modulation of CYP3A4.
Nat Commun, 16:3423-3423, 2025

PubMed Abstract: Drug-drug interactions associate with concurrent uses of multiple medications. Cytochrome P450 (CYP) 3A4 metabolizes a large portion of marketed drugs. To maintain the efficacy of drugs metabolized by CYP3A4, pan-CYP3A inhibitors such as ritonavir are often co-administered. Although selective CYP3A4 inhibitors have greater therapeutic benefits as they avoid inhibiting unintended CYPs and undesirable clinical consequences, the high homology between CYP3A4 and CYP3A5 has hampered the development of such selective inhibitors. Here, we report a series of selective CYP3A4 inhibitors with scaffolds identified by high-throughput screening. Structural, functional, and computational analyses reveal that the differential C-terminal loop conformations and two distinct ligand binding surfaces disfavor the binding of selective CYP3A4 inhibitors to CYP3A5. Structure-guided design of compounds validates the model and yields analogs that are selective for CYP3A4 versus other major CYPs. These findings demonstrate the feasibility to selectively inhibit CYP3A4 and provide guidance for designing better CYP3A4 selective inhibitors.

PubMed: 40210880
DOI: 10.1038/s41467-025-58749-8

実験手法

X-RAY DIFFRACTION (3 Å)