Molecular dimensions of the substrate binding site of cytochrome P-448

Abstract

The molecular geometries of specific substrates, inhibitors and inducers of cytochrome P-448 activity were determined using computer-graphic techniques for use in defining the molecular dimensions of the substrate binding site of this enzyme. Specific substrates of cytochrome P-448 are essentially planar molecules characterised by a small depth and a large area/depth ratio. In contrast, compounds that do not serve as substrates of cytochrome P-448 are bulky, non-planar molecules characterised by small area/depth ratios and greater flexibility in molecular conformation. Specific inhibitors of cytochrome P-448 whose effect is mediated through interaction with the haem still meet the dimensional criteria for substrates indicating that they must also interact with the substrate binding-site, which is probably located in proximity to the haem. Inducers of cytochrome P-448 activity exhibit similar molecular geometries to the substrates from which it may be inferred that the cytosolic receptor associated with the induction of cytochrome P-448 activity is structurally related to the active site of the cytochrome. © 1986.