Our laboratory is pursuing a research program that focuses on structural studies of human viruses and viral proteins. All of the studies fit into an overall program in the laboratory that concentrates on using three-dimensional structural information to aid the design of antiviral agents and vaccines. Although there are significant obstacles to developing effective treatments for many important infectious diseases, increases in our fundamental knowledge about the molecular mechanisms of diseases and the agents that cause them are likely to be essential for success. In addition to the biomedical implications of this information, the structural data from these studies also have value for fundamental understanding of large molecular assemblies that involve interactions of proteins and nucleic acids. Given the size of the systems that are being studied, synchrotron radiation is required for obtaining reliable structures. During the previous project period we have solved several structures of 1 reverse transcriptase (RT) using diffraction data collected with synchrotron X-radiation at CHESS. We have also obtained initial solutions for two virus structures (coxsackievirus B1 complexed with an antiviral compound and an HRV14:HIV-1 immunogenic chimera). The structure of HIV-1 RT complexed with a dsDNA template-primer and a monoclonal antibody Fab fragment has been solved at 3.0 _ resolution (Jacobo-Molina et al., 1993) refined at 2.8 _ resolution (Ding et al., in preparation). The structures of HIV-1 RT complexed with a number of nonnucleoside RT inhibitors, including a-APA (Ding et al., 1995), 8-Cl TIBO (R86183) (Ding et al., 1995), and 9-Cl TIBO (R82913) (Das et al., submitted) have been solved at 2.8 _, 3.0 _, and 3.0 _ resolution, respectively. The structure of unliganded HIV-1 RT has also been determined and refined at 2.7 _ resolution (Hsiou et al., submitted). These will will serve as reference structures for the HIV-1 RT structural studies proposed here.
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