ArticleBiochemistry2012
Conformational adaptation of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 revealed upon binding multiple amlodipine molecules.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 73 citations in OpenAlex.
- 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
- Multilevel superposition for deciphering the conformational variability of protein ensembles.Briefings in bioinformatics · 2024Article
- Functional characterization of CYP1 enzymes: Complex formation, membrane localization and function.Journal of inorganic biochemistry · 2023Article
- Four Decades of Cytochrome P450 2B Research: From Protein Adducts to Protein Structures and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Mechanism of Melatonin Metabolism by CYP1A1: What Determines the Bifurcation Pathways of Hydroxylation versus Deformylation?The journal of physical chemistry. B · 2022Article
- Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 2. Modeling of Experimental Data.Drug metabolism and disposition: the biological fate of chemicals · 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
- Enzyme Kinetics of Oxidative Metabolism-Cytochromes P450.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Molecular determinant of substrate binding and specificity of cytochrome P450 2J2.Scientific reports · 2020Article
- CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design.Pharmacology & therapeutics · 2020Review
- So many roads traveled: A career in science and administration.The Journal of biological chemistry · 2020Article
- Ligand Access Channels in Cytochrome P450 Enzymes: A Review.International journal of molecular sciences · 2018Review
- Crystal Structure of CYP2B6 in Complex with an Efavirenz Analog.International journal of molecular sciences · 2018Article
- Interaction of drugs amlodipine and paroxetine with the metabolizing enzyme CYP2B4: a molecular dynamics simulation study.Journal of molecular modeling · 2018Article
- Use of Phenoxyaniline Analogues To Generate Biochemical Insights into the Interactio n of Polybrominated Diphenyl Ether with CYP2B Enzymes.Biochemistry · 2018Article
- Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.ACS chemical biology · 2017Article
- Effect of detergent binding on cytochrome P450 2B4 structure as analyzed by X-ray crystallography and deuterium-exchange mass spectrometry.Biophysical chemistry · 2016Article
- Article
- Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism.Molecular pharmacology · 2016Article
- Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?BioMed research international · 2016Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Structures of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 in complex with two molecules of the calcium channel blocker amlodipine have been determined by X-ray crystallography. The presence of two drug molecules suggests clear substrate access channels in each P450. According to a previously established nomenclature, amlodipine molecules were trapped in access pathway 2f in P450 2B6 and in pathway 2a or 2f in P450 2B4. These pathways overlap for part of the length and then diverge as they extend toward the protein surface. A previously described solvent channel was also found in each enzyme. The results indicate that key residues located on the surface and at the entrance of the substrate access channels in each of these P450s may play a crucial role in guiding substrate entry. In addition, the region of P450 2B6 and 2B4 involving helices B', F, F', and G' and part of helix G is substantially more open in the amlodipine complexes than in the corresponding 4-(4-chlorophenyl)imidazole complexes. The increased active site volume observed results from the major retraction of helices F, F', and B' and the β4 sheet region located close to the binding cavity to accommodate amlodipine. These structures demonstrate novel insight into distinct conformational states not observed with previous P450 2B structures and provide clear evidence of the substrate access channels in two drug-metabolizing P450s. In addition, the structures exhibit the versatility that can be exploited via in silico studies with other P450 2B6 ligands as large as raloxifene and itraconazole.
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