Human APOBEC3G(h A3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor(Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work...Human APOBEC3G(h A3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor(Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work, we constructed and optimized molecular models of the hA3G dimer and the h A3G–Vif complex. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the h A3G–Vif complex and the hA3G dimer. Biochemical analysis provided evidence suggesting that binding of Vif to hA3G results in steric blocking of hA3G dimerization, implying that monomeric hA3G serves as a substrate for Vif-mediated degradation.Furthermore, we presented evidence for the important roles of the loop7 motif, especially the central residues within the region, in hA3G dimerization, h A3G–Vif interaction, Vif-mediated hA3G degradation as well as subcellular localization of hA3G. This work highlights a multiple-task interface formed by loop7 motif, which regulates biological function of hA3G, thus providing the feasibility of the strategy of blocking Vif-mediated A3 G degradation by targeting the putative site around loop7.展开更多
APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting ...APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting the antiviral activity of A3G.Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development.Currently,there is an urgent need for understanding the three dimensional structure of full-length A3G.In this work,we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2(APO2)and the catalytic domain structure of A3G.Two compounds,IMB26 and IMB35,which have been shown to bind to A3G and block degradation by Vif,were docked into the A3G model and the binding modes were generated for further analysis.The results may be used to design or optimize molecules targeting Vif–A3G interaction,and lead to the development of novel anti-HIV drugs.展开更多
基金supported by 973 program (2012CB911102 CS)National Megaproject for Innovative Drugs (2012ZX09301002-001-015 and 2012ZX09301002-005-002 CS)+1 种基金National Mega-Project for Infectious Disease (2013ZX1000 4601-002 CS)The National Natural Science Foundation of China (81271844 ZJM and 31470272 CS)
文摘Human APOBEC3G(h A3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor(Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work, we constructed and optimized molecular models of the hA3G dimer and the h A3G–Vif complex. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the h A3G–Vif complex and the hA3G dimer. Biochemical analysis provided evidence suggesting that binding of Vif to hA3G results in steric blocking of hA3G dimerization, implying that monomeric hA3G serves as a substrate for Vif-mediated degradation.Furthermore, we presented evidence for the important roles of the loop7 motif, especially the central residues within the region, in hA3G dimerization, h A3G–Vif interaction, Vif-mediated hA3G degradation as well as subcellular localization of hA3G. This work highlights a multiple-task interface formed by loop7 motif, which regulates biological function of hA3G, thus providing the feasibility of the strategy of blocking Vif-mediated A3 G degradation by targeting the putative site around loop7.
基金part by 973 program(2012C B911102)the National S&T Major Special Project on Major New Drug Innovation(2012ZX09102101-018)the National S&T International Collaboration 2010DFA31580(J.D.J.)and 2010DFB30870(Q.J.).
文摘APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting the antiviral activity of A3G.Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development.Currently,there is an urgent need for understanding the three dimensional structure of full-length A3G.In this work,we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2(APO2)and the catalytic domain structure of A3G.Two compounds,IMB26 and IMB35,which have been shown to bind to A3G and block degradation by Vif,were docked into the A3G model and the binding modes were generated for further analysis.The results may be used to design or optimize molecules targeting Vif–A3G interaction,and lead to the development of novel anti-HIV drugs.
