Structures of cytochrome P450 enzymes

Abstract

The protein database has > 450 entries with P450 in the title and of these there are approximately 54 unique structures. Although this sample of unique structures is small relative to the large number of P450s in Nature, it now is clear that the overall P450-fold is highly conserved and restricted to P450s and a small handful of other heme–thiolate enzymes. These crystal structures exhibit adaptations that underlie interactions with specific protein partners and in eukaryotes contribute to membrane binding. A handful of structures now have been solved in both the substrate-free open and substrate-bound closed states, and, while the details may differ among P450s, the open/close motion is very similar and involves the same elements of secondary structure. While the open form is more flexible, and thus may sample a number of isoenergetic conformations, highly specific P450s have only one unique substrate-bound conformation. In sharp contrast, for drug-metabolizing P450s, those regions most important for the open/close equilibrium also can adapt to substrates of different sizes, shapes, and chemical properties and is a unique design feature of these nonspecific P450s. Critical to understanding precisely how and which regions are most adaptable in drug-metabolizing P450s are the increasing number of ligand-bound structures.