8EWS

Crystal structure of CYP3A4 bound to an inhibitor

8EWS の概要

• エントリーDOI: 10.2210/pdb8ews/pdb
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, {N-[([2,2'-bipyridin]-5-yl-kappa~2~N~1~,N~1'~)methyl]-3-(pyridin-4-yl)propanamide}bis[2-(quinolin-2-yl-kappaN)-1-benzothiophen-3-yl-kappaC~3~]iridium(1+), ... (4 entities in total)
• 機能のキーワード: cytochrome p450, cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-inhibitor complex, 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: 57405.55

構造登録者

Sevrioukova, I.F. (登録日: 2022-10-24, 公開日: 2023-02-01, 最終更新日: 2023-10-25)

主引用文献

Denison, M.,Ahrens, J.J.,Dunbar, M.N.,Warmahaye, H.,Majeed, A.,Turro, C.,Kocarek, T.A.,Sevrioukova, I.F.,Kodanko, J.J.
Dynamic Ir(III) Photosensors for the Major Human Drug-Metabolizing Enzyme Cytochrome P450 3A4.
Inorg.Chem., 62:3305-3320, 2023

PubMed Abstract: Probing the activity of cytochrome P450 3A4 (CYP3A4) is critical for monitoring the metabolism of pharmaceuticals and identifying drug-drug interactions. A library of Ir(III) probes that detect occupancy of the CYP3A4 active site were synthesized and characterized. These probes show selectivity for CYP3A4 inhibition, low cellular toxicity, values as low as 9 nM, and are highly emissive with lifetimes up to 3.8 μs in cell growth media under aerobic conditions. These long emission lifetimes allow for time-resolved gating to distinguish probe from background autofluorescence from growth media and live cells. X-ray crystallographic analysis revealed structure-activity relationships and the preference or indifference of CYP3A4 toward resolved stereoisomers. Ir(III)-based probes show emission quenching upon CYP3A4 binding, then emission increases following displacement with CYP3A4 inhibitors or substrates. Importantly, the lead probes inhibit the activity of CYP3A4 at concentrations as low as 300 nM in CYP3A4-overexpressing HepG2 cells that accurately mimic human hepatic drug metabolism. Thus, the Ir(III)-based agents show promise as novel chemical tools for monitoring CYP3A4 active site occupancy in a high-throughput manner to gain insight into drug metabolism and drug-drug interactions.

PubMed: 36758158
DOI: 10.1021/acs.inorgchem.3c00059

実験手法

X-RAY DIFFRACTION (2.15 Å)