Homology modelling of CYP3A4 from the CYP2C5 crystallographic template: analysis of typical CYP3A4 substrate interactions.
1. The results of homology modelling of cytochrome P4503A4 (CYP3A4), which is a human enzyme of major importance for the Phase 1 metabolism of drug substrates, from the CYP2C5 crystal structure is reported. 2. The overall homology between the two protein sequences was generally good (46%) with 24% of amino acid residues being identical and a 22% similarity between matched pairs in the CYP3A4 and CYP2C5 aligned sequences, thus indicating that CYP2C5 represents a viable template for modelling CYP3A4 by homology. 3. The CYP3A4 model appears to show consistency with the reported findings from the extensive site-directed mutagenesis studies already published. 4. Typical CYP3A4 substrates, such as midazolam, testosterone, nifedipine and verapamil, are shown to fit the putative active site of the enzyme structure in a manner consistent with their known positions of metabolism.
School of Biomedical and Molecular Sciences, University of Surrey, Guildford 2GU2 7XH, UK. d.lewis@surrey.ac.uk
D F V
DF
Lewis
B G
BG
Lake
M
M
Dickins
P S
PS
Goldfarb
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013255:Steroid 21-Hydroxylase / Q000737:chemistry*; D013379:Substrate Specificity
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; C510163:CYP3A4 protein, human