Use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships of mammalian cytochromes P450

Life Sci. 1997;61(26):2507-20. doi: 10.1016/s0024-3205(97)00717-0.

Abstract

In recent years, homology modeling has become an important tool to study cytochrome P450 function, especially in conjunction with experimental approaches such as site-directed mutagenesis. Molecular models of mammalian P450s can be constructed based on crystal structures of four bacterial enzymes, P450cam, P450 BM-3, P450terp and P450eryF, using molecular replacement or consensus methods. In a model built by molecular replacement, the coordinates are copied from those of a given template protein, while consensus methods utilize more then one protein as a template and are based on distance geometry calculations. The models can be used to identify or confirm key residues, evaluate enzyme-substrate interactions and explain changes in protein stability and/or regio- and stereospecificity of substrate oxidation upon residue substitution by site-directed mutagenesis. P450 models have also been utilized to analyze binding of inhibitors or activators, as well as alterations in inhibition and activation due to residue replacement.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / physiology*
  • Models, Molecular
  • Molecular Structure
  • Mutagenesis, Site-Directed*
  • Sequence Homology*
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme System