X-ray crystallographic studies of malaria parasite proteins. (360G-Wellcome-063057_Z_00_B)

Malaria is a widespread health problem and remains a major killer. Although a tremendous body of data exists on the biology of malaria, three-dimensional structure information on key parasite proteins is scant. I propose to set up a research operation within the International Centre for Genetic Engineering and Biotechnology, New Delhi directed at using X-ray crystallography to elucidate the atomic structure of key malaria proteins. An understanding of the structural principles underlying these proteins will be of pivotal importance in biological and therapeutic progress. The proposed X-ray crystallographic studies will form the core of a multi-disciplinary approach in which structural information feeds back into functional studies. Amongst the initial targets for over-expression, purification, and crystallisation are Pfg27 (sexual stage protein), TRAP (Thrombospondin related anonymous protein), and Duffy-Binding-like domains. All biochemical and most crystallographic experiments are expected to be conducted in New Delhi. Where necessary, crystallographic diffraction data will be collected at various international synchrotron facilities. The proposed work will be carried out using established methodologies in which I have considerable experience. These structure determinations will contribute fundamentally to malaria biology, and may facilitate development of new anti-malarials.