Protein dynamics and imidazole binding in cytochrome P450 enzymes

Abstract

P450 (cytochrome P450) enzymes have major roles in the biosynthesis of endogenous factors such as steroids and eicosanoids, in the termination of the action of endogenous factors such as retinoic acid, in the metabolism of most drugs and xenobiotics and in the generation of toxic and carcinogenic products. Understanding the determinants of the substrate and inhibitor specificities of these enzymes is important for drug design. The crystallographic analysis of the deformability of two bacterial P450 active sites associated with the binding of azole (a class of inhibitors with an imidazole or triazole ring that co-ordinates to the haem iron) inhibitors described in the present study illustrates the importance of protein conformational malleability in the binding of imidazole derivatives.