Structurally dissecting APOBEC3's for HIV-1 restriction and beyond

从结构上剖析 APOBEC3 的 HIV-1 限制及其他限制

• 批准号: 10082374
• 负责人: Celia A. Schiffer
• 金额: $ 70.23万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10082374
• 关键词: Active Sites; Address; Antiviral Agents; Binding; Biological Assay; Biophysics; Catalytic Domain; Cell Nucleus; Chemicals; Chemistry; Collaborations; Complement; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Crystallization; Cytidine Deaminase; DNA; DNA Viruses; Data; Deamination; Dependovirus; Dinucleoside Phosphates; Double Stranded DNA Virus; Drug Design; Engineering; Ensure; Enzymatic Biochemistry; Enzymes; Epitopes; Family; Future; Genome; Genomics; Goals; HIV; HIV-1; Head Cancer; Hepatitis B Virus; Herpesviridae; Human; Human Papillomavirus; Immune system; Knowledge; Laboratories; Letters; Libraries; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mutation; Natural Immunity; Neck Cancer; Nuclear; Nucleic Acids; Oligonucleotides; Pan Genus; Positioning Attribute; RNA; Reagent; Research; Retrotransposon; Retroviridae; Roentgen Rays; Role; Series; Single Stranded DNA Virus; Site; Source; Specificity; Structure; Substrate Specificity; Surface; System; Therapeutic; Translating; Variant; Viral Genome; Virion; Virus Diseases; adaptive immunity; chemotherapy; design; experience; inhibitor/antagonist; interdisciplinary approach; intermolecular interaction; malignant breast neoplasm; molecular modeling; overexpression; particle; pathogen; structural biology; structured data; therapeutic development; tumor; ubiquitin-protein ligase; vif Gene Products; virology

Structurally dissecting APOBEC3s for HIV-1 restriction and beyond The human immune system protects us against pathogens but can cause problems when the system goes awry. Implicated in both innate and adaptive immunity, the AID/APOBEC family of enzymes are cytidine deaminases with differential roles of still limited understanding. A subset of APOBEC3s (A3s) were initially discovered to potently restrict HIV-1, including A3G, A3F and A3H. These restrictive enzymes are so potent that HIV evolved the “virion infectivity factor” protein Vif to counter this restriction by hijacking an E3 ubiquitin ligase and specifically targeting A3s for degradation. Subsequent research has revealed that A3’s ability to respond and restrict viral infection is by inducing hypermutations in the viral genome, which is not limited to HIV but extends to other retroviruses and retrotransposons. A3s also restrict DNA viruses, including nuclear replicating ssDNA viruses such as adeno-associated virus and dsDNA viruses such as hepatitis B virus, herpes viruses and HPV. However, A3 activity can be a double-edged sword. If not properly regulated, DNA-editing APOBECs that also have access to the nucleus can deaminate self-genomes, potentially instigating cancer. When overexpressed, A3A, A3B and A3H have been described as a major endogenous source for mutations in various types of human cancer, such as breast, bladder, head and neck, cervical, and lung cancer. We hypothesize that A3s have unrealized therapeutic potentials, both as anti-viral targets through reactivating the natural anti-HIV function by blocking Vif binding and as targets for chemotherapy to restrict the genome diversity within tumors. In this proposal we are leveraging our complementary strengths through a multi-disciplinary approach combining structural biology, biophysics, enzymology, chemistry and virology, to characterize the molecular interactions and differential specificities of A3s to nucleic acids and HIV-1 Vif, which will provide epitopes that once characterized will be target sites for future therapeutic development.

从结构上剖析APOBEC3s对HIV-1的限制