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Chapter category: Bioinformatics
Clues from 3-dimensional Structure Analysis and Molecular Modelling: New Insights Into Cytochrome P450 Mechanisms and Functions
Chapter authors:
Karin Schleinkofer and Thomas Dandekar
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Cytochrome P450 is a focus of attention as it comprises one of the largest superfamilies
of enzyme proteins. Metabolization of many drugs is affected by cytochrome P450. It
is an attractive drug target, e.g., cytochrome P450s of Mycobacterium tuberculosis are
promising targets in the fight against tuberculosis. The structure provides new insights for
investigation of structure/mechanism of cytochrome P450, and for rational design of inhibitor
molecules. We will illustrate how biocomputing and bioinformatical techniques reveal details,
functions and further secrets of this exciting molecule. Molecular modelling along with
site-directed mutagenesis of P450 2B1 elucidated the molecular determinants of substrate
specifity. Regioselectivity of progesterone hydroxylation by cytochrome P450 2B1 was
reengineered based on the X-ray structure of cytochrome 2C5. Docking approaches rationalized
the regioselectivity of the reengineered cytochrome P450 2B1. Furthermore, by methods
of molecular dynamic simulations routes were identified by which substrates may enter into
and products exit from the active site of cytochrome P450.
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