ArticleDrug metabolism and disposition: the biological fate of chemicals2011
Structure and function of cytochromes P450 2B: from mechanism-based inactivators to X-ray crystal structures and back.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2011. 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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Who cites it
20 citing papers in PubMed.
- 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
- 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
- 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
- So many roads traveled: A career in science and administration.The Journal of biological chemistry · 2020Article
- Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.ACS chemical biology · 2017Article
- Roles of Residues F206 and V367 in Human CYP2B6: Effects of Mutations on Androgen Hydroxylation, Mechanism-Based Inactivation, and Reversible Inhibition.Drug metabolism and disposition: the biological fate of chemicals · 2016Article
- Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame.Drug metabolism reviews · 2016Review
- 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
- Inhibition of cytochrome P450 2B4 by environmentally persistent free radical-containing particulate matter.Biochemical pharmacology · 2015Article
- Structural and biophysical characterization of human cytochromes P450 2B6 and 2A6 bound to volatile hydrocarbons: analysis and comparison.Molecular pharmacology · 2015Article
- Insights into the role of substrates on the interaction between cytochrome b5 and cytochrome P450 2B4 by NMR.Scientific reports · 2015Article
- Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida.Toxicology and applied pharmacology · 2014Article
- Correlating structure and function of drug-metabolizing enzymes: progress and ongoing challenges.Drug metabolism and disposition: the biological fate of chemicals · 2014Review
- A model of the membrane-bound cytochrome b5-cytochrome P450 complex from NMR and mutagenesis data.The Journal of biological chemistry · 2013Article
- Structural diversity of eukaryotic membrane cytochrome p450s.The Journal of biological chemistry · 2013Review
- X-ray crystal structure of the cytochrome P450 2B4 active site mutant F297A in complex with clopidogrel: insights into compensatory rearrangements of the binding pocket.Archives of biochemistry and biophysics · 2013Article
- Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen.Biochimica et biophysica acta · 2012Article
- Crystal structure of human cytochrome P450 2D6 with prinomastat bound.The Journal of biological chemistry · 2012Article
- Analysis of Cytochrome P450 Conserved Sequence Motifs between Helices E and H: Prediction of Critical Motifs and Residues in Enzyme Functions.Journal of drug metabolism & toxicology · 2011Article
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Abstract
This article reviews work from the author dating back to 1978 and focuses on the structural basis of cytochrome P450 (P450) function using available contemporary techniques. Early studies used mechanism-based inactivators that bound to the protein moiety of hepatic P450s to try to localize the active site. Subsequent studies used cDNA cloning, heterologous expression, site-directed mutagenesis, and homology modeling based on multiple bacterial P450 X-ray crystal structures to predict the active sites of CYP2B enzymes with considerable accuracy. Breakthroughs in engineering and expression of mammalian P450s enabled us to determine our first X-ray crystal structure of ligand-free rabbit CYP2B4. To date, we have solved 11 CYP2B4 and three human CYP2B6 structures, which represent four significantly different conformations. The plasticity of CYP2B4 has been confirmed by deuterium exchange mass spectrometry and is substantiated by molecular dynamics simulations. In addition to major movement of secondary structure elements, more subtle reorientation of active site side chains, especially Phe206, Phe297, and Glu301, contributes to the ability of CYP2B enzymes to bind various ligands. Isothermal titration calorimetry has proven to be a useful tool for studying the thermodynamics of ligand binding to CYP2B4 and CYP2B6, and NMR has enabled study of ligand binding orientation in solution as an adjunct to X-ray crystallography. A major challenge remains to harness the power of the various approaches to facilitate prediction of CYP2B specificity and inhibition.
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