STRUCTURAL STUDY OF DISEASE RELATED FACTORS

疾病相关因素的结构研究

• 批准号: 8361650
• 负责人: Yong Xiong
• 金额: $ 4.7万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361650
• 关键词: Antiviral Agents; C-terminal; Cysteine; Disease; Funding; Grant; HIV-1; Human; Length; Membrane Proteins; National Center for Research Resources; Positioning Attribute; Principal Investigator; Research; Research Infrastructure; Resources; Source; Structure; United States National Institutes of Health; Virus; alpha helix; cost; dimer; flexibility; insight; mutant; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tetherin/BST2 is a type-II membrane protein that inhibits the release of a range of enveloped viruses, including HIV-1. We solved three crystal structures of human tetherin, including the full-length ectodomain, a triple cysteine mutant and an ectodomain truncation. These structures show that tetherin forms a continuous alpha helix encompassing almost the entire ectodomain. Tetherin helices dimerize into parallel coiled coils via interactions throughout the C-terminal portion of the ectodomain. A comparison of the multiple structures of the tetherin dimer reveals inherent constrained flexibility at two hinges positioned at residues A88 and G109. In the crystals, two tetherin ectodomain dimers associate into a tetramer by forming an antiparallel four-helix bundle at their N termini. This study provides detailed insight into the mechanisms by which this broad-spectrum antiviral restriction factor can function.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 Tetherin/BST2 是一种 II 型膜蛋白，可抑制一系列包膜病毒（包括 HIV-1）的释放。我们解析了人系链蛋白的三种晶体结构，包括全长胞外域、三重半胱氨酸突变体和胞外域截短。这些结构表明，tetherin 形成了几乎涵盖整个胞外域的连续 α 螺旋。系链蛋白螺旋通过整个胞外域 C 端部分的相互作用二聚成平行卷曲线圈。对系链蛋白二聚体的多个结构的比较揭示了位于残基 A88 和 G109 处的两个铰链处固有的受限灵活性。在晶体中，两个束缚蛋白胞外域二聚体通过在其 N 末端形成反向平行的四螺旋束而结合成四聚体。这项研究提供了对这种广谱抗病毒限制因子发挥作用的机制的详细见解。