Publication: Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations
Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations
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Müller, C. S., Knehans, T., Davydov, D. R., Bounds, P. L., von Mandach, U., Halpert, J. R., Caflisch, A., & Koppenol, W. H. (2015). Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations. Biochemistry, 54(3), 711–721. https://doi.org/10.1021/bi5011656
Abstract
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Abstract
Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-
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- Müller, Christian S
- Knehans, Tim
- Davydov, Dmitri R
- Bounds, Patricia L
- von Mandach, Ursula
- Halpert, James R
- Caflisch, Amedeo
- Koppenol, Willem H
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315230_149897
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Computational studies of ligand binding and allostery
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Müller, C. S., Knehans, T., Davydov, D. R., Bounds, P. L., von Mandach, U., Halpert, J. R., Caflisch, A., & Koppenol, W. H. (2015). Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations. Biochemistry, 54(3), 711–721. https://doi.org/10.1021/bi5011656
