PT - JOURNAL ARTICLE AU - Manish B Shah AU - Paul Ross Wilderman AU - Jingbao Liu AU - Hyun-Hee Jang AU - Qinghai Zhang AU - C. David Stout AU - James R. Halpert TI - Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison AID - 10.1124/mol.114.097014 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.114.097014 4099 - http://molpharm.aspetjournals.org/content/early/2015/01/13/mol.114.097014.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/01/13/mol.114.097014.full AB - X-ray crystal structures of complexes of CYP2B6 and CYP2A6 with the monoterpene sabinene revealed two distinct binding modes in the active sites. In CYP2B6, sabinene positioned itself with the putative oxidation site located closer to the heme iron. In contrast, sabinene was found in an alternate conformation in the more compact CYP2A6, where the larger hydrophobic side chains resulted in a significantly reduced active site cavity. Furthermore, results from isothermal titration calorimetry indicated a much more substantial contribution of favorable enthalpy to sabinene binding to CYP2B6 as opposed to CYP2A6, consistent with the previous observations with (+)-α-pinene. Structural analysis of CYP2B6 complexes with sabinene and the structurally similar (3)-carene and comparison with previously solved structures revealed how the movement of the F206 side chain influences the volume of the binding pocket. In addition, retrospective analysis of prior structures revealed that ligands containing -Cl and -NH functional groups adopted a distinct orientation in the CYP2B active site compared with other ligands. This binding mode may reflect the formation of Cl-π or NH-π bonds with aromatic rings in the active site, which serve as important contributors to protein-ligand binding affinity and specificity. Overall, the findings from multiple techniques illustrate how drug metabolizing CYP2B6 and CYP2A6 handle a common hydrocarbon found in the environment. The study also provides insight into the role of specific functional groups of the ligand that may influence the binding to CYP2B6.