MOLECULAR MODELING OF CYP3A4 FROM AN ALIGNMENT WITH CYP102 - IDENTIFICATION OF KEY INTERACTIONS BETWEEN PUTATIVE ACTIVE-SITE RESIDUES AND CYP3A-SPECIFIC CHEMICALS
Dfv. Lewis et al., MOLECULAR MODELING OF CYP3A4 FROM AN ALIGNMENT WITH CYP102 - IDENTIFICATION OF KEY INTERACTIONS BETWEEN PUTATIVE ACTIVE-SITE RESIDUES AND CYP3A-SPECIFIC CHEMICALS, Xenobiotica, 26(10), 1996, pp. 1067-1086
1. A structural model of CYP3A4 is reported on the basis of a novel am
ino acid sequence alignment between the CYP3 family and CYP102, a bact
erial P450 of known crystal structure. 2. Construction of the CYP3A4 m
odel from CYP102 is facilitated by the relatively high sequence homolo
gy between the two proteins (52 % homology; 27 % identity) with many c
onservative amino acid changes, yielding a structure of low internal e
nergy. 3. A considerable number of specific substrates, and some speci
fic inhibitors, are shown to occupy the putative CYP3A4 active site vi
a interactions with the same amino acid residues in almost all cases i
nvestigated. 4. The CYP3A4 model rationalizes the known positions of m
etabolism for many substrates of this major human P450 such that the r
oute of metabolism in novel development compounds can be predicted.