CRYSTALLOGRAPHIC ANALYSIS OF HIV-1 VIF IN COMPLEX WITH HUMAN HOST PROTEINS

HIV-1 VIF 与人类宿主蛋白复合物的晶体学分析

• 批准号: 8170268
• 负责人: Joseph E Wedekind
• 金额: $ 0.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170268
• 关键词: 26S proteasome; Acquired Immunodeficiency Syndrome; Amino Acids; Binding; Boxing; C-terminal; CD4 Positive T Lymphocytes; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Cullin Proteins; Data; Development; Drug resistance; Funding; Grant; HIV-1; Home environment; Human; Immune; Individual; Institution; Ligase; Molecular; Persons; Pharmaceutical Preparations; Polyubiquitination; Proteins; Public Health; Recruitment Activity; Research; Research Personnel; Resources; Source; Structure; Therapeutic; United States National Institutes of Health; Viral; Virus; Work; World Health Organization; citrate carrier; elongin B; novel; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The World Health Organization estimates 30-36 million persons are infected worldwide with the HIV-1 virus. Nearly as many individuals have died from AIDS since 1981. Although significant progress has been made in the development of new anti-viral therapies, new classes of drugs are required due to the emergence of drug resistance. Here we propose to determine the crystal structure of the HIV-1 factor Vif, which is essential for viral infectivity due to its ability to inactivate the innate immune factor APOBEC3G in CD4+ T cells. Vif functions in the infected host cell by recruiting APOBEC3G to a Cullin Ring Ligase (CRL) complex where the anti-viral factor undergoes polyubiquitination, and subsequent degradation by the 26S proteasome. The C-terminal 72 amino acids of Vif are necessary and sufficient to interact with the elongin (Elo)B and EloC proteins of the CRL via a divergent BC-box motif. We have prepared crystals of a ternary complex comprising the C-terminus of Vif bound to the human EloB/C proteins. In the short term, we require rapid access to synchrotron radiation to: (i) screen the numerous small crystals we have prepared at home in order to guide optimization efforts; and (ii) to collect native data for possible molecular replacement using the known EloB/C coordinates. The interaction between Vif and EloB/C represents a potentially novel target for new HIV-1 therapeutics. As such, this work has the potential to benefit public health.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构为 中心，但不一定是研究者所在的机构。 世界卫生组织估计，全世界有3000万至3600万人感染了HIV-1病毒。自1981年以来，几乎同样多的人死于艾滋病。 虽然在开发新的抗病毒疗法方面取得了重大进展，但由于耐药性的出现，需要新的药物类别。在这里，我们建议确定HIV-1因子Vif的晶体结构，该因子对于病毒感染性是必不可少的，因为其能够在CD 4 + T细胞中抑制先天免疫因子APOBEC 3G。Vif通过将APOBEC 3G募集到Cullin环连接酶（CRL）复合物中而在感染的宿主细胞中起作用，其中抗病毒因子经历多聚泛素化，随后被26 S蛋白酶体降解。 Vif的C-末端72个氨基酸是必需的，并且足以通过不同的BC-盒基序与CRL的延伸蛋白（Elo）B和EloC蛋白相互作用。 我们已经制备了包含与人EloB/C蛋白结合的Vif的C-末端的三元复合物的晶体。在短期内，我们需要快速获得同步辐射：（i）筛选我们在国内制备的许多小晶体，以指导优化工作;（ii）使用已知的EloB/C坐标收集可能的分子置换的天然数据。Vif和EloB/C之间的相互作用代表了新的HIV-1治疗剂的潜在新靶点。因此，这项工作有可能有益于公众健康。