B.A., Physics, Cambridge University, Cambridge, UK 1974
M.A., Physics, Cambridge University, Cambridge, UK, 1978
D. Phil., Molecular Biophysics, Oxford University, Oxford, UK, 1978
My research focuses on the structure and activity of regulatory proteins with critical roles in human diseases with the goal of improving health. My research expertise covers macromolecular crystallography, molecular modeling, bioinformatics and biochemical analyses. Much of my work is highly collaborative and interdisciplinary. One long-term project on HIV protease, with the aims of understanding HIV drug resistance and developing new therapies for AIDS, has been supported by NIH since 1993. Important collaborators are Robert Harrison, Department of Computer Science, Arun Ghosh at Purdue University, John Louis and Hiroaki Mitsuya at NIH. We reported the binding mode of the novel drug darunavir to HIV-1 protease prior to its clinical approval in 2006. Our research on HIV protease and its variants has revealed unique mechanisms for drug resistance illustrated in high to atomic resolution crystal structures, and informed the design of novel antiviral inhibitors for drug resistant HIV/AIDS. Other recent research covers human caspases, intracellular calcium sensors, and diverse bacterial enzymes implicated in key metabolic pathways with collaborators from the Departments of Biology and Chemistry (Giovanni Gadda, Chung-Dar Lu, Phang C. Tai, Jenny Yang, and Zehava Eichenbaum). Our X-ray crystal structures of several proteins have helped to elucidate enzyme mechanisms, characterize potential drug targets and improve sensor designs.
- Zhang, H., Wang, Y.-F., Shen, C.-H., Agniswamy, J., Rao, K.V., Xu, C.-X., Ghosh, A.K., Harrison, R.W., Weber, I.T. Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. (2013) J. Med. Chem. 56, 1074-83.
- Zhang, Y., Reddish, F., Tang, S., Zhou, Y., Wang, Y.-F., Yang, J.J., Weber, I.T. Structural Basis for Hand-Like Site of Calcium Sensor CatchER with Fast Kinetics. (2013) Acta Crystallographica D, in press.
- Agniswamy, J., Shen, C.-H., Aniana, A., Sayer, J.M., Louis, J.M., Weber, I.T. HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements. (2012) Biochemistry, 51, 2819-2828.
- Shen, C.-H., Tie, Y., Yu, X., Wang, Y.-F., Kovalevsky, A.Y., Harrison, R.W., Weber, I.T. Capturing the Reaction Pathway in Near-Atomic Resolution Crystal Structures of HIV-1 Protease. (2012) Biochemistry 51, 7726-32.
- Fu, G., Yuan, H., Li, C., Lu, C.D., Gadda, G., Weber, I.T. Conformational Changes and Substrate Recognition in Pseudomonas aeruginosa D-Arginine Dehydrogenase. (2010) Biochemistry 49, 8535-45.