Structural studies of biomolecules related to cancer and HIV-AIDS

Division Of Basic Sciences - Nci

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Abstract

A3G is a single-stranded DNA cytosine deaminase that can restrict HIV-1 infection by mutating HIV-1 genome. HIV-1 developed a counter defense mechanism by which virion infectivity factor (Vif) leads the degradation of A3G through ubiquitin-proteasome pathway. Our ultimate goal is to generate small compounds which inhibit the degradation of A3G. We have determined structures of two functional domains of A3G, including the VIf-binding domain and the catalytic domain. We are working toward the structure determination of the A3G-Vif E3 ubiquitin ligase complex that will provide epitopes to be targeted by small compounds which inhibit formation of the complex. The A3G-Vif E3 ubiquitin ligase complex contains 6 proteins, and therefore it is challenging for any structural study. We are developing and optimizing biochemical and spectroscopic techniques to overcome the challenge.