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Open AccessArticle

Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2

1
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, 75270 Paris CEDEX 06, France
2
Institute for Integrative Biology of the Cell (I2BC), DRF/Joliot/SB2SM, CEA, CNRS, Université Paris-Saclay, F-91198 Gif-sur-Yvette CEDEX, France
3
Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
*
Author to whom correspondence should be addressed.
Present address: ICOA, CNRS UMR 7311, Université d’Orléans, Orléans, France.
Int. J. Mol. Sci. 2018, 19(7), 2066; https://doi.org/10.3390/ijms19072066
Received: 11 June 2018 / Revised: 6 July 2018 / Accepted: 13 July 2018 / Published: 16 July 2018
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
The influence of Arginine 117 of human cytochrome P450 2J2 in the recognition of ebastine and a series of terfenadone derivatives was studied by site-directed mutagenesis. R117K, R117E, and R117L mutants were produced, and the behavior of these mutants in the hydroxylation of ebastine and terfenadone derivatives was compared to that of wild-type CYP2J2. The data clearly showed the importance of the formation of a hydrogen bond between R117 and the keto group of these substrates. The data were interpreted on the basis of 3D homology models of the mutants and of dynamic docking of the substrates in their active site. These modeling studies also suggested the existence of a R117-E222 salt bridge between helices B’ and F that would be important for maintaining the overall folding of CYP2J2. View Full-Text
Keywords: human cytochrome P450; CYP2J2; mutants; regioselectivity; inhibitor; homology modeling; docking human cytochrome P450; CYP2J2; mutants; regioselectivity; inhibitor; homology modeling; docking
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MDPI and ACS Style

Lafite, P.; André, F.; Graves, J.P.; Zeldin, D.C.; Dansette, P.M.; Mansuy, D. Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2. Int. J. Mol. Sci. 2018, 19, 2066.

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