ArticleThe Journal of biological chemistry2008
Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 163 citations in OpenAlex.
- Expanding the Biocatalytic Toolbox: A Singular P450 Enzyme Efficiently Produces Diverse Pharmaceutical Metabolites.ACS omega · 2026Article
- MOLEonline: a web-based tool for analysing channels, tunnels, and pores (2025 update).Bioinformatics (Oxford, England) · 2025Article
- Hydrogen-Bond-Assisted Catalysis: Hydroxylation of Paclitaxel by Human CYP2C8.Journal of the American Chemical Society · 2024Article
- Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism.Pharmacological reviews · 2024Review
- Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.Journal of natural products · 2024Article
- In Silico and Chromatographic Methods for Analysis of Biotransformation of Prospective Neuroprotective Pyrrole-Based Hydrazone in Isolated Rat Hepatocytes.Molecules (Basel, Switzerland) · 2024Article
- Mce1R of Mycobacterium tuberculosis prefers long-chain fatty acids as specific ligands: a computational study.Molecular diversity · 2023Article
- Recombinant Technologies Facilitate Drug Metabolism, Pharmacokinetics, and General Biomedical Research.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Functional Characterization of Allelic Variations of Human Cytochrome P450 2C8 (V181I, I244V, I331T, and L361F).International journal of molecular sciences · 2023Article
- Inhibition of CYP2C8 by Acyl Glucuronides of Gemfibrozil and Clopidogrel: Pharmacological Significance, Progress and Challenges.Biomolecules · 2022Review
- Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction UsingACS omega · 2022Article
- Generation of new inhibitors of selected cytochrome P450 subtypes-Computational and structural biotechnology journal · 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
- CYP2C9 and 3A4 play opposing roles in bioactivation and detoxification of diphenylamine NSAIDs.Biochemical pharmacology · 2021Article
- Deciphering Structural Alterations Associated with Activity Reductions of Genetic Polymorphisms in Cytochrome P450 2A6 Using Molecular Dynamics Simulations.International journal of molecular sciences · 2021Article
- Structure-Functional Analysis of Human Cytochrome P450 2C8 Using Directed Evolution.Pharmaceutics · 2021Article
- Molecular and Structural Evolution of Cytochrome P450 Aromatase.International journal of molecular sciences · 2021Article
- Enzyme Kinetics of Oxidative Metabolism-Cytochromes P450.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Crystal Structures of Drug-Metabolizing CYPs.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Although a crystal structure and a pharmacophore model are available for cytochrome P450 2C8, the role of protein flexibility and specific ligand-protein interactions that govern substrate binding are poorly understood. X-ray crystal structures of P450 2C8 complexed with montelukast (2.8 A), troglitazone (2.7 A), felodipine (2.3 A), and 9-cis-retinoic acid (2.6 A) were determined to examine ligand-protein interactions for these chemically diverse compounds. Montelukast is a relatively large anionic inhibitor that exhibits a tripartite structure and complements the size and shape of the active-site cavity. The inhibitor troglitazone occupies the upper portion of the active-site cavity, leaving a substantial part of the cavity unoccupied. The smaller neutral felodipine molecule is sequestered with its dichlorophenyl group positioned close to the heme iron, and water molecules fill the distal portion of the cavity. The structure of the 9-cis-retinoic acid complex reveals that two substrate molecules bind simultaneously in the active site of P450 2C8. A second molecule of 9-cis-retinoic acid is located above the proximal molecule and can restrain the position of the latter for more efficient oxygenation. Solution binding studies do not discriminate between cooperative and noncooperative models for multiple substrate binding. The complexes with structurally distinct ligands further demonstrate the conformational adaptability of active site-constituting residues, especially Arg-241, that can reorient in the active-site cavity to stabilize a negatively charged functional group and define two spatially distinct binding sites for anionic moieties of substrates.
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