Structural studies of biomolecules related to cancer and HIV-AIDS

Division Of Basic Sciences - Nci

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Abstract

APOBEC3G (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. In addition, we have determined co-srystal structure of the A3G catalytic domain-ssDNA complex. By using NMR and Molecular Dynamics simulations, we revealed the mechanism by which APOBEC3 proteins exclude RNA as a substrate for deamination. We have assigned NMR signals of Vif, and identified amino acid residues in the interfaces with A3G. We are determining the structure of the A3G-Vif E3 ubiquitin ligase complex, which will provide epitopes to be targeted by small compounds which inhibit formation of the complex. We are using cryoEM/cryoET to determine the structure of the A3G-Vif E3 ubiquitin ligase complex.