8DYC

Human CYP3A4 bound to a substrate

8DYC の概要

• エントリーDOI: 10.2210/pdb8dyc/pdb
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione, ... (5 entities in total)
• 機能のキーワード: substrate, complex, oxidoreductase, oxidoreductase-substrate complex, oxidoreductase/substrate
• 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: 56790.81

構造登録者

Sevrioukova, I.F. (登録日: 2022-08-04, 公開日: 2022-10-26, 最終更新日: 2023-10-18)

主引用文献

Sevrioukova, I.F.
Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Cytochrome P450 3A4 (CYP3A4) is a major human drug-metabolizing enzyme, notoriously known for its extreme substrate promiscuity, allosteric behavior, and implications in drug-drug interactions. Despite extensive investigations, the mechanism of ligand binding to CYP3A4 is not fully understood. We determined the crystal structure of CYP3A4 complexed with fluorol, a small fluorescent dye that can undergo hydroxylation. In the structure, fluorol associates to the substrate channel, well suited for the binding of planar polyaromatic molecules bearing polar groups, through which stabilizing H-bonds with the polar channel residues, such as Thr224 and Arg372, can be established. Mutagenesis, spectral, kinetic, and functional data confirmed the involvement but not strict requirement of Thr224 for the association of fluorol. Collectively, our data identify the substrate channel as a high-affinity ligand binding site and support the notion that hydrophobic ligands first dock to the nearby peripheral surface, before migrating to the channel and, subsequently, into the active site.

PubMed: 36293445
DOI: 10.3390/ijms232012591

実験手法

X-RAY DIFFRACTION (2.4 Å)