3TJS

Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir

Summary for 3TJS

• Entry DOI: 10.2210/pdb3tjs/pdb
• Related: 3NXU
• Related PRD ID: PRD_001003
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, N-[(2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]-N~2~-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-L-valinamide, ... (4 entities in total)
• Functional Keywords: monooxygenase, cytochrome p450, endoplasmic reticulum, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Single-pass membrane protein: P08684
• Total number of polymer chains: 1
• Total formula weight: 56954.10

Authors

Sevrioukova, I.F.,Poulos, T.L. (deposition date: 2011-08-24, release date: 2012-03-07, Last modification date: 2023-09-13)

Primary citation

Sevrioukova, I.F.,Poulos, T.L.
Interaction of human cytochrome P4503A4 with ritonavir analogs.
Arch.Biochem.Biophys., 520:108-116, 2012

PubMed Abstract: Ritonavir is a HIV protease inhibitor that also potently inactivates cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme. To better understand the mechanism of ligand binding and to find strategies for improvement of the inhibitory potency of ritonavir, currently administered to enhance pharmacokinetics of other anti-HIV drugs that are quickly metabolized by CYP3A4, we compared the manner of CYP3A4 interaction with the drug and two analogs lacking either the heme-ligating thiazole nitrogen or the entire thiazole group. Based on the kinetic, mutagenesis and structural data, we conclude that: (i) the active site residue Arg212 assists binding of all investigated compounds and, thus, may play a more prominent role in metabolic transformation of xenobiotics than previously thought, (ii) peripheral binding of ritonavir limits the heme coordination rate and complicates the binding kinetics, (iii) association of ritonavir-like type II ligands is driven by heme coordination whereas hydrophobic forces define the binding mode, and (iv) substitution of one phenyl group in ritonavir with a smaller hydrophobic moiety could prevent steric clashing and, hence, increase the affinity and inhibitory potency of the drug.

PubMed: 22410611
DOI: 10.1016/j.abb.2012.02.018

Experimental method

X-RAY DIFFRACTION (2.25 Å)