Relations structure - Fonction dans la superfamille des Cytochromes P450

Cytochromes P450 (CYP) are monoxygenase enzymes involved in biotransformations of exogenous compounds in detoxification processes, but also in intoxication by generation of reactive species. CYP3A4, the most abundant isoform present in human liver, is responsible for the metabolisation of more than 60% of drugs used in therapy, leading to unwanted drug-drug interactions. The knowledge and understanding of mechanisms underlying substrate recognition and transformation is of outstanding interest for setting up reliable predictive tools in pharmaceutical companies. Achievement of CYP models by homology modeling is however limited by the high diversity of sequences in this superfamily. An original method based on the identification of Common Structural Blocks (CSB) within the family, is proposed here to rebuild structural models despite their low sequence identity. CSBs define a common fold of the CYPs and are used as a structural signature of the superfamily. A multiple alignment tool able to align successive profiles (calculated in each CSB) on the CYP sequences of unknown structure, has been developed to make use of the structural information beneath the CSBs, in one hand to give reliable multiple alignments used in homology modeling, and in the other hand, to search for new CYP sequences in databanks or genomes. When the structural model is obtained, in silico mutation experiments can be performed to monitor changes in the behavior of the protein towards its specifics substrates. A successful example is shown through CYP2B6 case, in which mutations suggested by the model led to significant increase of its affinity towards a specific substrate used in chemotherapy.