ArticleThe Journal of biological chemistry2019
Active-site differences between substrate-free and ritonavir-bound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
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Who cites it
20 citing papers in PubMed, 45 citations in OpenAlex.
- Decoding the selective chemical modulation of CYP3A4.Nature communications · 2025Article
- Theoretical Study on the Metabolic Mechanism of Heptachlor in Human Cytochrome P450 Enzymes.International journal of molecular sciences · 2025Article
- Characterization of CYP3A5 Selective Inhibitors for Reaction Phenotyping of Drug Candidates.The AAPS journal · 2024Article
- Review
- Differential Effects of Clotrimazole on X-Ray Crystal Structures of Human Cytochromes P450 3A5 and 3A4.Drug metabolism and disposition: the biological fate of chemicals · 2023Article
- Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms.Genes · 2023Review
- The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Review
- Article
- The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?International journal of molecular sciences · 2022Review
- Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.International journal of molecular sciences · 2022Article
- Structural characterization of the homotropic cooperative binding of azamulin to human cytochrome P450 3A5.The Journal of biological chemistry · 2022Article
- Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future.Advances in pharmacology (San Diego, Calif.) · 2022Article
- Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5.Journal of the American Chemical Society · 2021Article
- Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations.International journal of molecular sciences · 2021Article
- Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7.International journal of molecular sciences · 2021Article
- Tryptophan-75 Is a Low-Energy Channel-Gating Residue that Facilitates Substrate Egress/Access in Cytochrome P450 2D6.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Crystal Structures of Drug-Metabolizing CYPs.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications.Journal of medicinal chemistry · 2020Article
- Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.Journal of medicinal chemistry · 2020Article
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Cytochrome P450 (CYP) 3A4 is a major contributor to hepatic drug and xenobiotic metabolism in human adults. The related enzyme CYP3A5 is also expressed in adult liver and has broader age and tissue distributions. However, CYP3A5 expression is low in most Caucasians because of the prevalence of an allele that leads to an incorrectly spliced mRNA and premature termination of translation. When expressed, CYP3A5 expands metabolic capabilities and can augment CYP3A4-mediated drug metabolism, thereby reducing drug efficacy and potentially requiring dose adjustments. The extensive role of CYP3A4 in drug metabolism reflects in part the plasticity of the substrate-free enzyme to enlarge its active site and accommodate very large substrates. We have previously shown that the structure of the CYP3A5-ritonavir complex differs substantially from that of the CYP3A4-ritonavir complex. To better understand whether these differences are conserved in other CYP3A5 structures and how they relate to differential plasticity, we determined the X-ray crystallographic structure of the CYP3A5 substrate-free complex to 2.20 Å resolution. We observed that this structure exhibits a much larger active site than substrate-free CYP3A4 and displays an open substrate access channel. This reflected in part a lower trajectory of the helix F-F' connector in CYP3A4 and more extensive π-CH interactions between phenylalanine residues forming the roof of the active-site cavity than in CYP3A5. Comparison with the CYP3A5-ritonavir complex confirmed conserved CYP3A5 structural features and indicated differences in plasticity between CYP3A4 and CYP3A5 that favor alternative ritonavir conformations.
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Registered trials
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