The use of isomeric testosterone dimers to explore allosteric effects in substrate binding to cytochrome P450 CYP3A4

Journal of Inorganic Biochemistry
I G DenisovJames R Kincaid

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 of two steroid molecules, which can assume multiple possible configurations inside the substrate binding pocket of monomeric CYP3A4, can lead to active site structural changes that affect functional properties. Using resonance Raman spectroscopy, we have documented perturbations in the ferric and Fe-CO states by these substrates, and compared these results with effects caused by binding of monomeric TST. While the binding of trans-TST2 yields results similar to those obtained with monomeric TST, the binding of cis-TST2 is much tighter and results in significantly more pro...Continue Reading

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Citations

Oct 4, 2016·International Journal of Biological Macromolecules·P ChanphaiH A Tajmir-Riahi
Feb 9, 2017·Chemical Reviews·Ilia G Denisov, Stephen G Sligar
Mar 25, 2017·Bioconjugate Chemistry·Vanja Polic, Karine Auclair
Jun 20, 2017·Biochimica Et Biophysica Acta. Proteins and Proteomics·Julie Ducharme, Karine Auclair

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