Synthetic peptide mimics of a predicted topographical interaction surface: the cytochrome P450 2B1 recognition domain for NADPH-cytochrome P450 reductase |
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Authors: | Omata Y Dai R Smith S V Robinson R C Friedman F K |
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Affiliation: | (1) Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland, 20892;(2) Present address: Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan;(3) Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland, 20892 |
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Abstract: | In order to identify the cytochrome P450-binding domain for NADPH-cytochrome P450 reductase, synthetic peptide mimics of predicted surface regions of rat cytochrome P450 2B1 were constructed and evaluated for inhibition of the P450-reductase interaction. A peptide corresponding to residues 116–134, which includes the C helix, completely inhibited reductase-mediated benzphetamine demethylation by purified P450 2B1. Replacement of Arg-125 by Glu yielded a noninhibitory peptide, suggesting that this residue significantly contributes to the reductase-P450 interaction. Additional P450 peptides were prepared which correspond to combinations of regions distant in primary sequence, but predicted to be spatially proximate. A peptide derived from segments of the C and L helices was a more potent inhibitor than peptides derived from either segment alone. This topographically designed peptide not only inhibited P450 2B1 in its purified form, but also when membrane-bound in rat liver microsomes. The peptide also inhibited microsomal aryl hydrocarbon hydroxylase, aniline hydroxylase, and erythromycin demethylase activities derived from other P450s. These results indicate that the C and L helices contribute to a reductase-binding site common to multiple P450s, and present a peptide mimic for this region that is useful for inhibition of P450-mediated microsomal activities. |
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Keywords: | Protein structure protein-protein interactions peptide mimics cytochrome P450 drug metabolism |
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