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: 10682566
• 负责人: Celia A. Schiffer
• 金额: $ 65.08万
• 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/10682566
• 关键词: Active Sites; Address; Binding; Biological Assay; Biophysics; Catalytic Domain; Cell Nucleus; Chemicals; Chemistry; Collaborations; Complement; Complex; Cryo-electron tomography; Cryoelectron Microscopy; 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 and Neck Cancer; Hepatitis B Virus; 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; Nuclear; Nucleic Acids; Oligonucleotides; Pan Genus; Positioning Attribute; RNA; Reagent; Research; Retrotransposon; Retroviridae; Roentgen Rays; Role; Series; Single Stranded DNA Virus; Single-Stranded DNA; Site; Source; Specificity; Structure; Substrate Specificity; Surface; System; Therapeutic; Translating; Variant; Viral; Viral Genome; Virion; Virus; 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.

HIV-1限制及以上APOBEC3的结构解剖 人类的免疫系统保护我们免受病原体的侵袭，但在以下情况下可能会引发问题 系统出了问题。AID/APOBEC与先天免疫和获得性免疫有关 酶家族是胞苷脱氨酶，其不同作用仍然有限 理解。最初发现APOBEC3(A3)的一个子集可以有效地限制 HIV-1，包括A3G、A3F和A3H。这些限制性酶是如此强大，以至于艾滋病毒 通过劫持E3，进化出了“病毒感染性因子”蛋白质Vif来对抗这种限制 泛素连接酶，并专门针对A3s进行降解。随后的研究发现 A3透露，S的应答和限制病毒感染的能力是通过诱导 病毒基因组的过度突变，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还可以限制DNA病毒，包括核病毒 复制单链DNA病毒，如腺相关病毒和双链DNA病毒，如 乙肝病毒、疱疹病毒和人乳头瘤病毒。然而，A3的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 核可以使自身基因组脱氨基，潜在地引发癌症。当过度表达时， A3A、A3B和A3H已被描述为 各种人类癌症，如乳腺癌、膀胱癌、头颈部癌、宫颈癌和肺癌 癌症。我们假设A3具有尚未实现的治疗潜力，两者都是作为抗病毒的。 通过阻断Vif结合和AS来重新激活天然的抗HIV功能 限制肿瘤内基因组多样性的化疗靶点。在这份提案中，我们 正在通过多学科结合的方法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 A3s对核酸和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点 发展。

项目成果

Crystal Structure of a Soluble APOBEC3G Variant Suggests ssDNA to Bind in a Channel that Extends between the Two Domains.

• DOI: 10.1016/j.jmb.2020.10.020
• 发表时间: 2020-11-20
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Maiti A;Myint W;Delviks-Frankenberry KA;Hou S;Kanai T;Balachandran V;Sierra Rodriguez C;Tripathi R;Kurt Yilmaz N;Pathak VK;Schiffer CA;Matsuo H
• 通讯作者: Matsuo H

Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state.

• DOI: 10.1038/s41467-022-34752-1
• 发表时间: 2022-11-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Maiti, Atanu;Hedger, Adam K.;Myint, Wazo;Balachandran, Vanivilasini;Watts, Jonathan K.;Schiffer, Celia A.;Matsuo, Hiroshi
• 通讯作者: Matsuo, Hiroshi