4I4H
Crystal structure of CYP3A4 ligated to pyridine-substituted desoxyritonavir
Summary for 4I4H
| Entry DOI | 10.2210/pdb4i4h/pdb |
| Related | 3NXU 4I4G |
| Descriptor | Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, pyridin-3-ylmethyl [(2R,5S)-5-{[N-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-D-valyl]amino}-1,6-diphenylhexan-2-yl]carbamate (3 entities in total) |
| Functional Keywords | monooxygenase, cytochrome p450 reductase, cytochrome b5, endoplasmic reticulum, cytochrome p450, 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 | 57073.22 |
| Authors | Sevrioukova, I.F.,Poulos, T.L. (deposition date: 2012-11-27, release date: 2013-04-24, Last modification date: 2023-09-20) |
| Primary citation | Sevrioukova, I.F.,Poulos, T.L. Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir. J.Med.Chem., 56:3733-3741, 2013 Cited by PubMed Abstract: Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association. PubMed: 23586711DOI: 10.1021/jm400288z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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