Structural Biology and Macromolecular Crystallography

For life to manifest itself in all its glory, a multitude of biomolecules have to carry out their functions precisely. A variety of methods have been developed to try and understand how biomolecules operate. Among these methods macromolecular crystallography is unique because it provides a visual snapshot of the biomolecule. Additionally through elegant experimental design, many biomolecules can be crystallized in their functional states. This provides an accurate picture -at the atomic level- of the chemical basis of their bioactivity. In case of proteins, the knowledge of the 3-dimensional arrangement of atoms in space provides valuable insight into the relationship between primary amino-acid sequence and tertiary functional structure. This knowledge can be crucial in all endeavors to predict the structure and therefore function of uncharacterized proteins.

We aim to understand the chemical basis for the specific functions of molecules involved in RNA virus replication and DNA repair. X-ray crystallography will be the primary tool and other biophysical methods will also be used to answer specific questions or validate structural observations. Macromolecules and macromolecular complexes will be identified for crystallization and the subsequent structures will be analyzed in the context of available genetic and biochemical data to make detailed inferences about the chemical basis of their functions. These inferences will also be validated using biophysical, biochemical and genetic methods. Overall, this approach will provide detailed insight into how these biomolecules function and also enable design of strategies for the manipulation of their bioactivity, if required.

Selected Publications:

1. Namadurai S, Jain D, Kulkarni DS, Tabib CR, Friedhoff P, Rao DN, Nair DT. The C-terminal domain of the MutL homolog from Neisseria gonorrhoeae forms an inverted homodimer. PLoS One. 2010 Oct 28;5(10):e13726.

2. Nair, D.T., Johnson, R. E., Prakash, S., Prakash, L. and Aggarwal, A. K. (2005) Rev1 employs a novel mechanism of DNA synthesis using a protein template. Science. 309:2219.

3. Nair, D.T., Johnson, R. E., Prakash, S., Prakash, L. and Aggarwal, A. K. (2004) Replication by human DNA polymerase-iota occurs by Hoogsteen base- pairing. Nature. 430:377.