Cytochrome P450 2C9 (CYP2C9) is a major enzyme involved in human drug metabolism. Despite its importance and resulting extensive study, elements of substrate selectivity and specificity in CYP2C9 are still under investigation, owing largely to the size and flexibility of its substrate binding pocket. To gain new insights on conformational heterogeneity in substrate binding, we have used infrared spectroscopy of vibrational probes inserted site-specifically using amber suppression methodology at various positions throughout the binding pocket. These probes allow us to observe local environmental changes that occur as a result of binding various substrates, indicating the position and potential heterogeneity of binding. In conjunction with other biophysical characterization, our infrared spectral data allows us to propose models for the binding of various substrates which take into account conformational flexibility in CYP2C9. These models in turn support investigation into hydroxylation specificity, important for understanding drug metabolism in the biological context.

Infrared spectroscopy of vibrational probes to investigate substrate binding in cytochrome P450 2C9

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