Download MendeleyHalogen-pi Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.
Shah, M.B., Liu, J., Zhang, Q., Stout, C.D., Halpert, J.R.(2017) ACS Chem Biol 12: 1204-1210
- PubMed: 28368100
- DOI: https://doi.org/10.1021/acschembio.7b00056
- Primary Citation of Related Structures:
5UAP, 5UDA, 5UEC, 5UFG - PubMed 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 ? 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.
Organizational Affiliation:
School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
