7UAZ

Crystal structure of human CYP3A4 with the caged inhibitor

Summary for 7UAZ

• Entry DOI: 10.2210/pdb7uaz/pdb
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, (N-[([2,2'-bipyridin]-5-yl-kappa~2~N~1~,N~1'~)methyl]-3-{[(pyridin-3-yl)methyl]sulfanyl}propanamide)bis[2-(pyridin-2-yl-kappaN)phenyl-kappaC~1~]iridium (3 entities in total)
• Functional Keywords: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 57239.36

Authors

Sevrioukova, I.F. (deposition date: 2022-03-14, release date: 2022-08-31, Last modification date: 2023-10-18)

Primary citation

Denison, M.,Steinke, S.J.,Majeed, A.,Turro, C.,Kocarek, T.A.,Sevrioukova, I.F.,Kodanko, J.J.
Ir(III)-Based Agents for Monitoring the Cytochrome P450 3A4 Active Site Occupancy.
Inorg.Chem., 61:13673-13677, 2022

PubMed Abstract: Cytochromes P450 (CYPs) are a superfamily of enzymes responsible for biosynthesis and drug metabolism. Monitoring the activity of CYP3A4, the major human drug-metabolizing enzyme, is vital for assessing the metabolism of pharmaceuticals and identifying harmful drug-drug interactions. Existing probes for CYP3A4 are irreversible turn-on substrates that monitor activity at specific time points in end-point assays. To provide a more dynamic approach, we designed, synthesized, and characterized emissive Ir(III) and Ru(II) complexes that allow monitoring of the CYP3A4 active-site occupancy in real time. In the bound state, probe emission is quenched by the active-site heme. Upon displacement from the active site by CYP3A4-specific inhibitors or substrates, these probes show high emission turn-on. Direct probe binding to the CYP3A4 active site was confirmed by X-ray crystallography. The lead Ir(III)-based probe has nanomolar and high selectivity for CYP3A4, efficient cellular uptake, and low toxicity in CYP3A4-overexpressing HepG2 cells.

PubMed: 35994607
DOI: 10.1021/acs.inorgchem.2c02587

Experimental method

X-RAY DIFFRACTION (2.65 Å)