Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 IIIA4

Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2000-01, Vol.14 (1), p.93-116
Main Authors: De Rienzo, F, Fanelli, F, Menziani, M C, De Benedetti, P G
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biochemistry
Comparative analysis
Crystallography, X-Ray
Cytochrome P-450 CYP1A2 - chemistry
Cytochrome P-450 CYP1A2 - genetics
Cytochrome P-450 CYP1A2 - metabolism
Cytochrome P-450 CYP2D6 - chemistry
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 - metabolism
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Drug Design
Enzymes
Humans
Microsomes - enzymology
Mixed Function Oxygenases - chemistry
Mixed Function Oxygenases - genetics
Mixed Function Oxygenases - metabolism
Models, Molecular
Molecular Sequence Data
Protein Conformation
Sequence Homology, Amino Acid
Substrate Specificity
Substrates
Thermodynamics
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Summary:Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.
ISSN:0920-654X
1573-4951
DOI:10.1023/a:1008187802746