Coupling Crystallography and Computational Biochemistry in Understanding Heme Enzyme Structure and Function

摘要

Computational methods and crystallography have been coupled to study structure-function relationships in cytochrome c peroxidase (CCP) and nitric oxide synthase (NOS). NOS is an important drug target and the structural details of NOS-inhibitor interactions are essential if structure-based drug design is to be of any use in the development of therapeutic agents targeted to NOS. The structure of 7-nitroindazole, a potent NOG inhibitor, complexed to one NOS isoform left some ambiguity in the precise orientation of the inhibitor. Various computational approaches were used to resolve this ambiguity as well as revealing the energetic basis for tight binding. With CCP site directed mutagenesis, crytallography and various computational tools have been used to understand why CCP is unique among the peroxidase in its ability to stabilize a trytophan cation radical during catalysis.