ArticleThe Journal of biological chemistry2018
Membrane-embedded substrate recognition by cytochrome P450 3A4.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Lipid nanoparticles as active biointerfaces: From membrane interaction to systemic dysregulation.Acta pharmaceutica Sinica. B · 2026Review
- Insights into the molecular mechanism of endoplasmic reticulum monooxygenase-induced ferroptosis revealed by in situ Raman spectroscopy.Analytical and bioanalytical chemistry · 2026Article
- 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
- From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4.Journal of computer-aided molecular design · 2025Article
- Extended Sampling of Macromolecular Conformations from Uniformly Distributed Points on Multidimensional Normal Mode Hyperspheres.Journal of chemical theory and computation · 2024Article
- Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome P450 2B4.Protein science : a publication of the Protein Society · 2024Article
- Small angle scattering reveals the orientation of cytochrome P450 19A1 in lipoprotein nanodiscs.Journal of inorganic biochemistry · 2024Article
- 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
- Induced Fit Describes Ligand Binding to Membrane-Associated Cytochrome P450 3A4.Molecular pharmacology · 2023Article
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site.International journal of molecular sciences · 2022Article
- Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells.International journal of molecular sciences · 2022Article
- Effect of Human Cytochrome P450 2D6 Polymorphism on Progesterone Hydroxylation.European journal of drug metabolism and pharmacokinetics · 2022Article
- Structural characterization of the homotropic cooperative binding of azamulin to human cytochrome P450 3A5.The Journal of biological chemistry · 2022Article
- Preparative Production of Functionalized (Biomolecules · 2022Article
- Time-dependent inhibition of CYP3A4-mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism.International journal of clinical pharmacology and therapeutics · 2021Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Structural Dynamics of Cytochrome P450 3A4 in the Presence of Substrates and Cytochrome P450 Reductase.Biochemistry · 2021Article
- Dynamics and Mechanism of Binding of Androstenedione to Membrane-Associated Aromatase.Biochemistry · 2020Article
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
Cytochrome P450 3A4 (CYP3A4) is the dominant xenobiotic-metabolizing enzyme in the liver and intestine and is involved in the disposition of more than 50% of drugs. Because of its ability to bind multiple substrates, its reaction kinetics are complex, and its association with the microsomal membrane confounds our understanding of how this enzyme recognizes and recruits diverse substrates. Testosterone (TST) hydroxylation is the prototypical CYP3A4 reaction, displaying positive homotropic cooperativity with three binding sites. Here, exploiting the capability of accelerated molecular dynamics (aMD) to sample events in the millisecond regime, I performed >25-μs aMD simulations in the presence of three TST molecules. These simulations identified high-occupancy surface-binding sites as well as a pathway for TST ingress into the CYP3A4 active site originating in the membrane. Adaptive biasing force analysis of the latter pathway revealed a metastable intermediate that could constitute a third binding site at high TST concentrations. Prompted by the observation that interactions between TST and the G'-helix mobilize the ligand into the active site, a free-energy analysis of TST distribution in the membrane was conducted and revealed that the depth of the G'-helix is optimal for extracting TST. In summary, these simulations confirm separate, but adjacent substrate-binding sites within the enzyme and the existence of an auxiliary TST-binding site. The broader impact of these simulations is that they support a mechanism in which cytochromes P450 directly recruit membrane-solubilized substrates.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.