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: 10461788
• 负责人: Celia A. Schiffer
• 金额: $ 66.31万
• 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/10461788
• 关键词: Active Sites; Address; 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; Viral Genome; Virion; Virus Diseases; adaptive immunity; chemotherapy; design; experience; inhibitor; interdisciplinary approach; intermolecular interaction; malignant breast neoplasm; molecular modeling; overexpression; particle; pathogen; structural biology; 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.

在结构上解剖HIV-1限制及以后的APOBEC3S 人类免疫系统可以保护我们免受病原体的侵害，但可能会引起问题 系统出了问题。援助/apobec以先天性和适应性免疫实施 酶家族是胞苷死亡蛋白，其作用仍然有限 理解。最初发现了一个亚apobec3s（A3S）的子集有可能限制 HIV-1，包括A3G，A3F和A3H。这些限制性酶是如此潜力，以至于艾滋病毒 进化了“视力感染因子”蛋白VIF，以劫持E3来应对这种限制 泛素连接酶，专门针对降解的A3。随后的研究 揭示了A3的反应能力和限制病毒感染的能力是通过诱导的 病毒基因组中的高温，不限于HIV，而是延伸到其他 逆转录病毒和逆转座子。 A3还限制了包括核在内的DNA病毒 复制ssDNA病毒，例如腺相关病毒和dsDNA病毒，例如 肝炎病毒，疱疹病毒和HPV。但是，A3活动可以是双刃 剑。如果不正确调节，则可以访问的DNA编辑APOBEC 细胞核会脱氨基，可能会煽动癌症。过表达时， A3a，A3b和A3H已被描述为突变的主要内源性来源 各种类型的人类癌症，例如乳房，膀胱，头颈，颈椎和肺 癌症。我们假设A3具有未实现的治疗潜力，均为抗病毒 通过阻止VIF结合和AS来重新激活自然抗HIV功能的目标 化学疗法的靶标限制了肿瘤内的基因组多样性。在这个建议中，我们 通过多学科的方法结合利用我们的完善优势 结构生物学，生物物理学，酶学，化学和病毒学，以表征 A3s对核酸和HIV-1 VIF的分子相互作用以及差异规格，它们 将提供一旦特征的表位将是未来治疗的目标部位 发展。