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.

结构剖析 APOBEC3 的 HIV-1 限制及其他限制 人体免疫系统可以保护我们免受病原体侵害，但在以下情况下可能会引起问题： 系统出了问题。 AID/APOBEC 与先天免疫和适应性免疫有关 酶家族是胞苷脱氨酶，其不同作用仍然有限 理解。 APOBEC3 (A3) 的一个子集最初被发现可以有效限制 HIV-1，包括A3G、A3F和A3H。这些限制性酶是如此有效，以至于艾滋病毒 进化出“病毒粒子感染因子”蛋白 Vif，通过劫持 E3 来对抗这种限制 泛素连接酶并专门针对 A3 进行降解。后续研究有 揭示 A3 反应和限制病毒感染的能力是通过诱导 病毒基因组中的超突变，不仅限于艾滋病毒，还延伸到其他 逆转录病毒和逆转录转座子。 A3 还限制 DNA 病毒，包括核病毒 复制 ssDNA 病毒，例如腺相关病毒和 dsDNA 病毒，例如 乙型肝炎病毒、疱疹病毒和HPV。然而，A3 活动可能是一把双刃剑 剑。如果没有适当的监管，DNA 编辑 APOBEC 也可以访问 细胞核可以使自身基因组脱氨基，从而可能引发癌症。当过度表达时， A3A、A3B 和 A3H 已被描述为突变的主要内源来源。 各种类型的人类癌症，如乳腺癌、膀胱癌、头颈癌、宫颈癌和肺癌 癌症。我们假设 A3 具有未实现的治疗潜力，既可以作为抗病毒药物，也可以作为抗病毒药物。 通过阻断 Vif 结合来重新激活天然抗 HIV 功能，从而达到目标 化疗的目标是限制肿瘤内的基因组多样性。在这个提案中我们 正在通过多学科方法结合利用我们的互补优势 结构生物学、生物物理学、酶学、化学和病毒学，以表征 A3 与核酸和 HIV-1 Vif 的分子相互作用和差异特异性， 将提供表位，一旦表征将成为未来治疗的靶位点 发展。