Human APOBEC3G is capable of altering the HIV genome by deaminating cDNA cytosines to uracils. This activity can genetically inactivate HIV. As a counter-defense mechanism, HIV promotes protein degradation of APOBEC3G. Degradation requires that the HIV virion infectivity factor (Vif) protein interacts with APOBEC3G. Current studies have revealed substantial genetic and biochemical details of this host-pathogen conflict, but an atomic level understanding is still lacking. Therefore, the major objectives of this research are to obtain a structural understanding of the DNA cytosine deaminase activity of APOBEC3G and of the APOBEC3G -Vif interaction. These objectives will be achieved through the following specific aims: (I) we will achieve an atomic-level understanding of APOBEC3G and how it catalyzes the DNA cytosine deamination reaction, and (II) we will obtain an atomic-level knowledge that will explain how APOBEC3G is recognized by Vif. These primary objectives will be met by combining genetic, biochemical, biophysical and structural (NMR) approaches. These studies will produce the first structure of a polynucleotide cytosine deaminase, and the resulting structural insights will take us several steps closer to achieve our long-term goal of developing therapeutic methods for enhancing APOBEC3G function. Human APOBEC3G (A3G) is capable of altering the HIV genome by deaminating cDNA cytosines to uracils. This activity can genetically inactivate the virus. As a counter-defense mechanism, HIV promotes the ubiquitin-mediated protein degradation of A3G. Degradation requires that A3G interacts with the HIV virion infectivity factor (Vif) protein. Current studies have revealed substantial genetic and biochemical details of this host-pathogen conflict, but an atomic level understanding is still lacking. Therefore, the major objectives of this research are to obtain a structural understanding of the DNA cytosine deaminase activity of A3G and of the A3G-Vif interaction. ? ? ?
| Kouno, Takahide; Luengas, Elizabeth M; Shigematsu, Megumi et al. (2015) Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G. Nat Struct Mol Biol 22:485-91 |
| Harjes, Stefan; Solomon, William C; Li, Ming et al. (2013) Impact of H216 on the DNA binding and catalytic activities of the HIV restriction factor APOBEC3G. J Virol 87:7008-14 |
| Fukunishi, Yoshifumi; Hongo, Saki; Lintuluoto, Masami et al. (2012) Free Energy Profile of APOBEC3G Protein Calculated by a Molecular Dynamics Simulation. Biology (Basel) 1:245-59 |
| Chiba, Junya; Kouno, Takahide; Aoki, Shun et al. (2012) Electrochemical direct detection of DNA deamination catalyzed by APOBEC3G. Chem Commun (Camb) 48:12115-7 |
| Dewan, Varun; Liu, Tao; Chen, Kuan-Ming et al. (2012) Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction. ACS Chem Biol 7:761-9 |
| Dang, Ying; Abudu, Aierken; Son, Sungmo et al. (2011) Identification of a single amino acid required for APOBEC3 antiretroviral cytidine deaminase activity. J Virol 85:5691-5 |
| Shandilya, Shivender M D; Nalam, Madhavi N L; Nalivaika, Ellen A et al. (2010) Crystal structure of the APOBEC3G catalytic domain reveals potential oligomerization interfaces. Structure 18:28-38 |
| Harjes, Elena; Gross, Phillip J; Chen, Kuan-Ming et al. (2009) An extended structure of the APOBEC3G catalytic domain suggests a unique holoenzyme model. J Mol Biol 389:819-32 |
| Norton, Jolanna; Matsuo, Hiroshi; Sturla, Shana J (2009) Synthesis of deoxytetrahydrouridine. J Org Chem 74:2221-3 |
| Chen, Kuan-Ming; Martemyanova, Natalia; Lu, Yongjian et al. (2007) Extensive mutagenesis experiments corroborate a structural model for the DNA deaminase domain of APOBEC3G. FEBS Lett 581:4761-6 |
