Objectif Plasmodium falciparum cell cycle regulators are promising targets for novel anti-malarial drug design. This application is firmly based in the post-genomic era where the identification of novel drug targets is greatly facilitated by the availability of the P. falciparum genomic databases. P. falciparum cell cycle regulators are promising drug targets because of their predicted essential roles in regulating the pathogen's life-cycle. We have determined the structure of PfPK5. the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. A comparison of CDK structures from these two evolutionarily remote organisms suggests that the fold and the mechanism of inactivation of monomeric CDKs are highly conserved. The first aim of this project is to employ X-ray crystallographic studies to guide the development of potent and selective small molecule ATP-competitive inhibitors of P. falciparum protein kinase 5 (PfPK5), a member of the P. falciparum cyclin-dependent protein kinase family. Homologues of this enzyme in other eukaryotes play an essential role in regulating cell cycle progression. These compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for anti-malarial drug development. The second aim of the project is to employ biochemical and biophysical methods to characterise CDK/cyclin complexes. This will explore the evolutionary conservation of the structural mechanisms that regulate the eukaryotic cell cycle. The final aim is to characterise P. falciparum cyclin 4 (Pfcyc-4) a novel member of the cyclin family that shows a distinct pattern of expression in the erythrocytic stages of the parasite's life cycle. Champ scientifique medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health scienceshealth sciencesinfectious diseasesmalariamedical and health sciencesbasic medicinemedicinal chemistrynatural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Mots‑clés drug design fuctional genomics malaria Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Thème(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Appel à propositions FP6-2002-MOBILITY-5 Voir d’autres projets de cet appel Régime de financement EIF - Marie Curie actions-Intra-European Fellowships Coordinateur CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Contribution de l’UE Aucune donnée Adresse University Offices, Wellington Square OXFORD Royaume-Uni Voir sur la carte Coût total Aucune donnée
