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USE OF HOMOLOGY MODELING IN CONJUNCTION WITH SITE-DIRECTED MUTAGENESIS FOR ANALYSIS OF STRUCTURE-FUNCTION RELATIONSHIPS OF MAMMALIAN CYTOCHROMES P450
Ist Teil von
Life sciences (1973), 1997, Vol.61 (26), p.2507-2520
Ort / Verlag
Netherlands: Elsevier Inc
Erscheinungsjahr
1997
Link zum Volltext
Quelle
Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)
Beschreibungen/Notizen
In recent years, homology modeling has become an important tool to study cytochrome P450 function, especially in conjunction with experimental approaches such as site-directed mutagenesis. Molecular models of mammalian P450s can be constructed based on crystal structures of four bacterial enzymes, P450cam, P450 BM-3, P450terp and P450eryF, using molecular replacement or consensus methods. In a model built by molecular replacement, the coordinates are copied from those of a given template protein, while consensus methods utilize more then one protein as a template and are based on distance geometry calculations. The models can be used to identify or confirm key residues, evaluate enzyme-substrate interactions and explain changes in protein stability and/or regio- and stereospecificity of substrate oxidation upon residue substitution by site-directed mutagenesis. P450 models have also been utilized to analyze binding of inhibitors or activators, as well as alterations in inhibition and activation due to residue replacement.