This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Apoptosis is a fundamental process for life. Bcl-2 family proteins are the key regulators of this process. Our group published the discovery of the first small molecule inhibitor of Bcl-2 and demonstrated its use as a new anticancer strategy. In this proposal, we try to get the complex structure of Bcl-2 proteins with natural and unnatural inhibitors. The structural information can provide us insights into protein-small molecule interaction and guide our rational design of new inhibitors. CXCR4 and CCR5 are two main chemokine receptors used by HIV-1 infection. These chemokine receptors play an important role in HIV pathology. Recently, we synthesized a set of new anti-HIV chemokines by incorporating D-amino acids into natural chemokines sequences such as SDF-1alpha, vMIP-II. To probe the structure features of the new synthetic chemokines, we try to determine the crystal structures of these new chemokines. By doing so, we expect to figure out the structure-function of the anti-HIV chemokines and further to design small molecular drug to mimic the critical structural part of the chemokines and combat the HIV virus.
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