Structural and functional studies of protein targets related to infectious diseases (host-pathogen interactions) and cancers
Proteins are important biological macromolecules playing vital and integral roles in all living systems. Proteins are implicated as causes of many diseases. X-ray crystallography enables us to determine three-dimensional structures of proteins, and thus to understand their functional roles and contributions to diseases. It is important to study proteins that play key roles in diseases. This can be achieved by structural and structure based functional both in vitro (mutagenesis and biophysical / biochemical / biological) and in vivo studies.
My laboratory focuses on a number of host and pathogen proteins that play important roles in infectious diseases. The project encompasses studies of molecular mechanisms of bacterial and viral pathogenesis in the context of disease processes. To this end, we are investigating several targets to understand the biological question on how virulence factors of Gram-negative bacteria initiate the infection process. To address this question we study the type III secretion system (T3SS) and type VI secretion systems (T6SS). Similarly in the viral pathogenesis, we are investigating the mechanism of host interaction and neutralization of hepatitis E virus (HEV).
We are also studying the structural basis for the mechanism of action of a number of cancer related proteins and their interactions to understand the key steps in the signal transduction pathways.
The long-term goal of our group is to illuminate outstanding challenges in the area of infectious diseases through host-pathogen interactions and cancers to provide new avenues for addressing them towards drug design and development.
Gu Y, Tang X, Zhang X, Song C, Zheng M, Wang K, Zhang J, Ng MH, Hew CL, Li S, Xia N, Sivaraman J. Structural Basis for the Neutralization of Hepatitis E Virus by a Cross-genotype Antibody. Cell Res. 2015 May;25(5):604-20.
Abhilash Padavannil, Chacko Jobichen, Yang Qinghua, J Seetharaman, Adrian Velazquez-Campoy, Liu Yang, Shen Q. Pan, Sivaraman J, Dimerization of VirD2 Binding Protein is essential for Agrobacterium induced tumor formation in plants PLoS Pathogens 2014 Mar 13;10(3):e1003948
Abhilash Padavannil, Chacko Jobichen, Erez Mills, Adrian Velazquez-Campoy, Mo Li, Ka Yin Leung, Yu Keung Mok, Ilan Rosenshine, Sivaraman J Structure of GrlR-GrlA Complex that Prevents GrlA Activation of Virulence Genes Nature Communications 2013;4:2546. doi: 10.1038/ncomms3546
Thangavelu K, Pan CQ, Karlberg T, Balaji G, Uttamchandani M, Suresh V, Schüler H, Low BC, Sivaraman J (2012) Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. PNAS (2012). May 15;109(20):7705-10.
Mukherjee M, Chow SY, Yusoff P, Seetharaman J, Ng C, Sinniah S, Koh XW, Asgar NF, Li D, Yim D, Jackson RA, Yew J, Qian J, Iyu A, Lim YP, Zhou X, Sze SK, Guy GR, Sivaraman J (2012) Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO J (2012) Jan 17; 31(5):1308-19.
Tang, X., Yang, C., Gu, Y., Song, C., Zhang, X., Wang, Y., Zhang, J., Hew, C.L., Li, S., Xia, N. Sivaraman, J (2011) Structural basis for the neutralization and genotype specificity of hepatitis E virus. PNAS. 108, 10266-10271.
Zhou, X., Kini, R.M. and Sivaraman, J., (2011) Application of isothermal titration calorimetry and column chromatography for identification of biomolecular targets. Nature Protocols, 6, 158-165. Faculty of 1000 (F1000) recommended this paper as a most important article in biology and medical research publications.
Husain, N., Obranic, S., Koscinski, L., Seetharaman, J., Babic, F., Bujnicki, J.M., Maravic-Vlahovicek, G. and Sivaraman, J., (2011) Structural basis for the methylation of A1408 in 16S rRNA by a panaminoglycoside resistance methyltransferase NpmA from a clinical isolate and analysis of the NpmA interactions with the 30S ribosomal subunit. Nucleic Acids Research, 39, 1903-1918.
Husain, N., Tkaczuk, K.L., Tulsidas, S.R., Kaminska, K.H., Cubrilo, S., Maravic-Vlahovicek, G., Bujnicki, J.M. and Sivaraman, J., (2010) Structural basis for the methylation of G1405 in 16S rRNA by aminoglycoside resistance methyltransferase Sgm from an antibiotic producer: a diversity of active sites in m7G methyltransferases. Nucleic Acids Research, 38, 4120-4132.
Li, S., Tang, X., Seetharaman, J., Yang, C., Gu, Y., Zhang, J., Du, H., Shih, J.W., Hew, C.L., Sivaraman, J and Xia. (2009) Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus-host interaction. PLoS Pathogens, 5, e1000537.
Chua, T.K., Bujnicki, J.M., Tan, T.C., Huynh, F., Patel, B.K. and Sivaraman, J., (2008) The structure of sucrose phosphate synthase from Halothermothrix orenii reveals its mechanism of action and binding mode. Plant Cell, 20, 1059-1072.
Ng, C., Jackson, R.A., Buschdorf, J.P., Sun, Q., Guy, G.R. and Sivaraman, J., (2008) Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO J., 27, 804-816.
Sunita, S., Purta, E., Durawa, M., Tkaczuk, K.L., Swaathi, J., Bujnicki, J.M. and Sivaraman, J., , (2007) Functional specialization of domains tandemly duplicated within 16S rRNA methyltransferase RsmC. Nucleic Acids Research, 35, 4264-4274.
Jobichen, C., Li, M., Yerushalmi, G., Tan, Y.W., Mok, Y.K., Rosenshine, I., Leung, K.Y. and Sivaraman, J., (2007) Structure of GrlR and the implication of its EDED motif in mediating the regulation of type III secretion system in EHEC. PLoS Pathogens, 3, e69.