3NXU
Crystal structure of human cytochrome P4503A4 bound to an inhibitor ritonavir
Summary for 3NXU
| Entry DOI | 10.2210/pdb3nxu/pdb |
| Related | 1TQN 1W0E 1W0F 1W0G 2J0D 2V0M |
| Related PRD ID | PRD_001001 |
| Descriptor | Cytochrome P450 3A4, DIMETHYL SULFOXIDE, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total) |
| Functional Keywords | alpha beta protein, cytochrome p450 fold, hemoprotein, monooxygenase, cytochrome p450 reductase, 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 | 2 |
| Total formula weight | 114106.62 |
| Authors | Sevrioukova, I.F.,Poulos, T.L. (deposition date: 2010-07-14, release date: 2010-10-20, Last modification date: 2023-09-06) |
| Primary citation | Sevrioukova, I.F.,Poulos, T.L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc.Natl.Acad.Sci.USA, 107:18422-18427, 2010 Cited by PubMed Abstract: Ritonavir is a HIV protease inhibitor routinely prescribed to HIV patients that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. By inhibiting CYP3A4, ritonavir increases plasma concentrations of other anti-HIV drugs oxidized by CYP3A4 thereby improving clinical efficacy. Despite the importance and wide use of ritonavir in anti-HIV therapy, the precise mechanism of CYP3A4 inhibition remains unclear. The available data are inconsistent and suggest that ritonavir acts as a mechanism-based, competitive or mixed competitive-noncompetitive CYP3A4 inactivator. To resolve this controversy and gain functional and structural insights into the mechanism of CYP3A4 inhibition, we investigated the ritonavir binding reaction by kinetic and equilibrium analysis, elucidated how the drug affects redox properties of the hemoprotein, and determined the 2.0 Å X-ray structure of the CYP3A4-ritonavir complex. Our results show that ritonavir is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase. PubMed: 20937904DOI: 10.1073/pnas.1010693107 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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