Homology modelling of human CYP1A2 based on the CYP2C5 crystallographic template structure.
1. The results of homology modelling of human cytochrome P4501A2 (CYP1A2) based on the CYP2C5 crystal structure are reported. It exhibits improved sequence homology relative to that of CYP102. 2. It was demonstrated that many selective substrates for CYP1A2 could fit within the putative active site of the enzyme, and in orientations which agree with documented evidence for CYP1A2-mediated metabolism. 3. Furthermore, a number of amino acid residues lining the haem pocket have been shown, via site-directed mutagenesis, to have an influence on substrate metabolism, and these experimental findings from the literature are consistent with the modelled interactions for selective substrates. 4. The binding affinities of several CYP1A2 substrates have also been calculated from the CYP1A2 active site interactions and they agree closely with experimental values.
Lewis
D F V
DF
Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK. d.lewis@surrey.ac.uk
Lake
B G
BG
Dickins
M
M
Ueng
Y-F
YF
Goldfarb
P S
PS
D000595:Amino Acid Sequence; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D018360:Crystallography, X-Ray; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D000072467:Cytochrome P450 Family 2; D005399:Fishes; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D013045:Species Specificity; D013255:Steroid 21-Hydroxylase / Q000737:chemistry*
D008055:Lipids; D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; D019388:Cytochrome P-450 CYP1A2; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase