Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor apolipoprotein B mRNA-editing enzyme,catalytic polypeptide-like 3G |
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Institution: | 1. Laboratory of Molecular Imaging Probes, Department of Radiology, University of Massachusetts Medical School,Worcester,MA;2. Volgograd State Medical University, Volgograd, Russia;3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,Moscow, Russia;4. Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology and Chemistry Department, Moscow, Russia;5. PharmaIN Corp., Bothell, WA |
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Abstract: | Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), is a human anti-virus restriction protein which works deaminase-dependently and -independently. A3G is known to be ubiquitinated by HIV-1 viral infectivity factor (Vif) protein, leading to proteasomal degradation. A3G contains two zinc ions at the N-terminal domain and the C-terminal domain. Four lysine residues, K297, K301, K303, and K334, are known to be required for Vif-mediated A3G ubiquitination and degradation. Previously, we reported compound SN-1, a zinc chelator that increases steady-state expression level of A3G in the presence of Vif. In this study, we prepared Biotin-SN-1, a biotinylated derivative of SN-1, to study the SN-1–A3G interaction. A pull-down assay revealed that Biotin-SN-1 bound A3G. A zinc-abstraction experiment indicated that SN-1 binds to the zinc site of A3G. We carried out a SN-1–A3G docking study using molecular operating environment. The calculations revealed that SN-1 binds to the C-terminal domain through Zn2+, H216, P247, C288, and Y315. Notably, SN-1-binding covers the H257, E259, C288, and C291 residues that participate in zinc-mediated deamination, and the ubiquitination regions of A3G. The binding of SN-1 presumably perturbs the secondary structure between C288 and Y315, leading to less efficient ubiquitination. |
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Keywords: | APOBEC3G Host anti-viral factor HIV Zinc Biotin–avidin technology Molecular docking |
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