Cytochrome P450 (CYP) is a super-family of monoozygenase enzymes that function in major detoxification and biosynthetic pathways in almost every living organism. Continuous wave electron paramagnetic resonance (CW EPR) and pulsed EPR methods have been used in previous studies to characterize low-spin direct coordination and water-bridging binding motifs of two CYP isoforms in complex with specific drugs at the heme active site. In this study, a variety of CYP/drug complexes were studied in order to identify trends in ligand field shifts that indicate the presence of specific binding motifs. CW EPR spectra of the active site were analyzed for four CYP450 isoforms (CYP3A4, CYP2C9D, CYP125A1 and CYP51B1) each in a resting state with no drug bound or in complex with one of twenty different drugs. EasySpin 5.0, a program in MATLAB, was used to simulate the CW EPR spectra and produced fitted gz, gy, and gx-values, which correspond to the molecular orientation of the active site. CW EPR spectra with low field shifted gz peaks were found to have three distinct clusters of subspecies and high field shifted gz peaks were found to have one cluster. These signature clusters include various isoform/drug complexes and point to similar binding motifs that are found throughout a wide variety of CYPs.

Identification of universal cytochrome P450 binding modes using continuous wave electron paramagnetic resonance spectroscopy

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.