Molecular modelling of CYP3A4 from an alignment with CYP102: identification of key interactions between putative active site residues and CYP3A-specific chemicals

Xenobiotica. 1996 Oct;26(10):1067-86. doi: 10.3109/00498259609167423.


1. A structural model of CYP3A4 is reported on the basis of a novel amino acid sequence alignment between the CYP3 family and CYP102, a bacterial P450 of known crystal structure. 2. Construction of the CYP3A4 model from CYP102 is facilitated by the relatively high sequence homology between the two protein (52% homology; 27% identity) with many conservative amino acid changes, yielding a structure of low internal energy. 3. A considerable number of specific substrates, and some specific inhibitors, are shown to occupy the putative CYP3A4 active site via interactions with the same amino acid residues in almost all cases investigated. 4. The CYP3A4 model rationalizes the known positions of metabolism for many substrates of this major human P450 such that the route of metabolism in novel development compounds can be predicted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins*
  • Binding Sites
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism
  • Electrochemistry
  • Humans
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / chemistry*
  • Mixed Function Oxygenases / metabolism
  • Models, Molecular*
  • Molecular Sequence Data
  • NADPH-Ferrihemoprotein Reductase
  • Protein Binding
  • Sequence Alignment
  • Substrate Specificity
  • Templates, Genetic


  • Bacterial Proteins
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • NADPH-Ferrihemoprotein Reductase
  • flavocytochrome P450 BM3 monoxygenases