Research Groups

Mammalian Biology: Structural and Computational Biology

Research Interests and Description

Research Interests

Protein structure, function and crystallography.

Description of Research

In the past six years we have established a strong group on Structural and Computational Biology at ICGEB, New Delhi. The Group has made many pivotal contributions to highlighting structural principles that govern molecular. The group has made a niche in structural biology of crucial malaria parasite proteins, and recent addition of two new investigators with expertise in membrane protein structure determination and NMR will further expand the scope of this group. The combined expertise in the group will therefore be in a position to link with new discoveries made in terms of molecular targets against infectious diseases like malaria and TB. Existing collaborations between the Malaria and the Structural Biology group has been tremendously successful. Our results so far have opened avenues for (a) investigations into new facets of parasite biology, and (b) design of inhibitors against critical parasite developmental stages.
Protein crystallographic studies of malaria parasite proteins
The laboratory takes a multi-disciplinary approach towards understanding malaria parasite proteins. We aim to highlight the principles that govern biological function of key parasite proteins. Towards this end, we rely extensively on bioinformatics, biochemistry, cell biology, molecular biology, parasitology and protein crystallography. Using multi-disciplinary approaches, we have been successful at elucidating structure-function relationships for several crucial parasite proteins, and we hope that these analyses will guide therapeutic developments against malaria. Complex life cycle of the malaria parasite necessitates having an elaborate protein repertoire which are tightly regulated. This requirement highlights two important enzymatic families whose main function is in protein translation, its fidelity and proof reading – (1) aminoacyl-tRNA synthetases and (2) D-amino acid tRNA deacylase. Structural studies on both these systems are likely to throw light on their mechanism of action, and may help in rational drug design against these. Amongst the many processes fundamentally important to the parasite, one involves packaging of DNA into nucleosomes and chromatin. Several specialized parasite proteins perform DNA compaction and we are working on two such proteins called Nucleosome Assembly Proteins (Pf-NAPz). These two proteins interact with other essential parasite proteins like histones to assemble and disassemble nucleosomes. Further, P. falciparum NAPz are important for cellular activities like DNA repair, DNA recombination and transcription. We have identified a role for PfNAPz in histone transport and nucleocytoplasmic shuttling. Therefore, we propose to investigate, in considerable detail, biological features of the two P. falciparum NAPz in order to further our understanding of the DNA packing process within the parasite.

Recent Publications

Yogavel, M., Gill, J., Sharma, A. 2009. Iodide-SAD, SIR and SIRAS phasing for structure solution of a nucleosome assembly protein. Acta Crystallogr D Biol Crystallogr. 65, 618-622

Gill, J., Chitnis, C.E., Sharma, A. 2009. Structural insights into chondroitin sulphate A binding Duffy-binding-like domains from Plasmodium falciparum: implications for intervention strategies against placental malaria. Malaria J. 8, 67

Mishra, P.C., Kumar, A., Sharma, A. 2009. Analysis of small nucleolar RNAs reveals unique genetic features in malaria parasites. BMC Genomics, 10, 68

Gill, J., Yogavel, M., Kumar, A., Belrhali, H., Jain, S. K., Rug, M., Brown, M., Maier A. G., Sharma, A. 2009. Crystal structure of malaria parasite nucleosome assembly protein: distinct modes of protein localization and histone recognition. J Biol Chem. 284, 10076-10087

Hora, R., Bridges, D. J., Craig, A., Sharma, A. 2009. Erythrocytic casein kinase II regulates cytoadherence of Plasmodium falciparum-infected red blood cells. J Biol Chem., 284, 6260-6269

Chitnis, C.E., Sharma, A. 2008. Targeting the Plasmodium vivax Duffy-binding protein.Trends Parasitol. 24, 29-34