Physical Sciences and Mathematics Commons^™

The Use Of Isomeric Testosterone Dimers To Explore Allosteric Effects In Substrate Binding To Cytochrome P450 Cyp3a4, Ilia G. Denisov, Piotr J. Mak, Yelena V. Grinkova, Dominic Bastien, Gervais Bérubé, Stephen G. Sligar, James R. Kincaid

Chemistry Faculty Research and Publications

Abstract: Cytochrome P450 CYP3A4 is the main drug-metabolizing enzyme in the human liver, being responsible for oxidation of 50% of all pharmaceuticals metabolized by human P450 enzymes. Possessing a large substrate binding pocket, it can simultaneously bind several substrate molecules and often exhibits a complex pattern of drug–drug interactions. In order to better understand structural and functional aspects of binding of multiple substrate molecules to CYP3A4 we used resonance Raman and UV–VIS spectroscopy to document the effects of binding of synthetic testosterone dimers of different configurations, cis-TST₂ and trans-TST₂. We directly demonstrate that the binding …