title: Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.
abstract: Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2.5 Å compared with the latter complex. The bromine in myrtenyl bromide π-bonded with Phe297 in CYP2B6, whereas the two major orientations in the active site mutant I114V exhibited bromine-π interactions with two additional residues, Phe108 and Phe115. Analysis of existing structures suggests that halogen-π interactions may be unique to the CYP2B enzymes within CYP family 2 but are also important for CYP3A enzymes.
authors.affiliation: School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
authors.forename: Manish B
authors.identifier: 0000-0001-8593-6446
authors.initials: MB
authors.lastname: Shah
authors.affiliation: School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
authors.forename: Jingbao
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Department of Integrative Structural and Computational Biology, The Scripps Research Institute , La Jolla, California, United States.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Department of Integrative Structural and Computational Biology, The Scripps Research Institute , La Jolla, California, United States.
authors.forename: C David
authors.initials: CD
authors.lastname: Stout
authors.affiliation: School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Halpert
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D065702:Cytochrome P-450 CYP2B6 / Q000737:chemistry*; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D039821:Monoterpenes / Q000737:chemistry; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D006219:Halogens; D039821:Monoterpenes; D065702:Cytochrome P-450 CYP2B6