ArticleProceedings of the National Academy of Sciences of the United States of America2006
Structural basis for ligand promiscuity in cytochrome P450 3A4.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 308 papers.
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308 citing papers in PubMed.
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- Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM.bioRxiv : the preprint server for biology · 2026Article
- Toxicity and DNA Adduct Formation Reinforce AI-Guided Prediction of Aflatoxin B1 Bioactivation in VERO E6 Cells.Toxins · 2026Article
- In Vitro Cytochrome P450 Interaction Profile and ADME Characterisation of Gold(I)-Triphenylphosphine Complexes with 6-Alkoxy-9-deazapurine Ligands.Pharmaceutics · 2026Article
- Thermostable ancestors enabled evolutionary diversification of promiscuous chemical defence enzymes.The EMBO journal · 2026Article
- MolViewStories: Interactive molecular storytelling.Protein science : a publication of the Protein Society · 2026Article
- Metabolic Stability of Fluorinated Small Molecules: A Physical Organic Chemistry Perspective.Journal of medicinal chemistry · 2026Review
- Binding Site Vectors Enable Mapping of Cytochrome P450 Functional Landscapes.Journal of chemical information and modeling · 2026Article
- A new metabolic path in type 3 rickets.The FEBS journal · 2026Review
- Lipid Dependence of CYP3A4 Activity in Nanodiscs.Biology · 2026Article
- Molecular dynamics simulations elucidate the role of the F-F' loop in substrate entry into CYP3A4.Communications chemistry · 2026Article
- Human Metabolism of Sirolimus Revisited.Metabolites · 2025Article
- Exploring Long Arm Amide-Linked Side Chains in the Design of Antifungal Azole Inhibitors of Sterol 14α-Demethylase (CYP51).Journal of medicinal chemistry · 2025Article
- Decoding the selective chemical modulation of CYP3A4.Nature communications · 2025Article
- From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4.Journal of computer-aided molecular design · 2025Article
- Article
- Theoretical Study on the Metabolic Mechanism of Heptachlor in Human Cytochrome P450 Enzymes.International journal of molecular sciences · 2025Article
- Theoretical Investigation of Cytochrome P450 Enzyme-Mediated Biotransformation Mechanism of BHPF: Unveiling the Metabolic Safety Aspects of an Alternative to BPA.Environment & health (Washington, D.C.) · 2025Article
- Extended Sampling of Macromolecular Conformations from Uniformly Distributed Points on Multidimensional Normal Mode Hyperspheres.Journal of chemical theory and computation · 2024Article
- Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol.Pharmaceutics · 2024Article
248 more citing papers are in PubMed but not listed here.
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2 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of approximately 50% of marketed drugs. It is also the isoform most often involved in unwanted drug-drug interactions. A better understanding of the molecular mechanisms governing CYP3A4-ligand interaction therefore would be of great importance to any drug discovery effort. Here, we present crystal structures of human CYP3A4 in complex with two well characterized drugs: ketoconazole and erythromycin. In contrast to previous reports, the protein undergoes dramatic conformational changes upon ligand binding with an increase in the active site volume by >80%. The structures represent two distinct open conformations of CYP3A4 because ketoconazole and erythromycin induce different types of coordinate shifts. The binding of two molecules of ketoconazole to the CYP3A4 active site and the clear indication of multiple binding modes for erythromycin has implications for the interpretation of the atypical kinetic data often displayed by CYP3A4. The extreme flexibility revealed by the present structures also challenges any attempt to apply computational design tools without the support of relevant experimental data.
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