Structural Biology Core

结构生物学核心

• 批准号: 7127928
• 负责人: STEPHEN COPLAN HARRISON
• 金额: $ 67.18万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127928
• 关键词: AIDS vaccines; HIV envelope protein; HIV envelope protein gp120; HIV infections; X ray crystallography; biomedical facility; biotechnology; conformation; cooperative study; cryoelectron microscopy; disulfide bond; glycoprotein structure; human immunodeficiency virus 1; microorganism immunology; monoclonal antibody; neutralizing antibody; structural biology; transfection /expression vector; vaccine development

The goals of the structural biology core are threefold: (1) to determine structures of the HIV envelope glycoprotein in its various conformations (and especially in the unliganded state found on the surface of a mature virion), in order to have as complete a "molecular movie" of its conformational transitions as possible; (2) to engage in collaborative structure determinations with investigators in the CHAVI project (in particular to answer questions about how molecular context influences immunogenicity of gp120 variable loops) or to help organize such collaborations with other laboratories when appropriate; (3) to communicate the complex picture of envelope conformational transformations to the rest of the HIV community and in particular to the other investigators in this CHAVI consortium. Specific aims include: (1) generating stabilized forms of unliganded HIV-1 gp120 for structural studies, by introducing disulfide bonds based on the recently determined structure of unliganded SIV gp120; (2) using the results of the first aim to produce stabilized gp140 trimers for structural studies; (3) using the results of the first two aims to analyze the immunogenic properties of the HIV envelope protein in its unliganded conformation. Depending on the outcome of other experiments in the CHAVI consortium, structures will be determined for certain Fab fragments from "broadly" neutralizing mAbs, in complex with peptide antigens or with gp120 or gp140 bearing the appropriate epitopes. There will be an ongoing effort to communicate the complexities of envelope conformational changes, through development of an interactive molecular animation that incorporates new structural data as they emerge.

结构生物学的核心目标有三个：（1）确定HIV包膜糖蛋白的各种构象的结构（特别是在成熟病毒体表面发现的无配体状态下），以便尽可能完整地拍摄其构象转变的“分子电影”;（2）与CHAVI项目的研究人员合作确定结构（特别是回答有关分子环境如何影响gp120可变环免疫原性的问题）或在适当时帮助组织与其他实验室的此类合作;（3）沟通复杂 这张照片的信封构象转换的其余部分的艾滋病毒社区，特别是其他研究人员在这个CHAVI财团。具体目标包括：（1）通过基于最近确定的未配体的SIV gp120的结构引入二硫键，产生用于结构研究的未配体的HIV-1 gp120的稳定形式;（2）使用第一个目的的结果产生用于结构研究的稳定的gp140三聚体;（3）利用前两者的结果分析HIV包膜蛋白在其未配体构象下的免疫原性。根据CHAVI联合体中其他实验的结果，将确定来自"广泛"中和mAb的某些Fab片段的结构，所述Fab片段与肽抗原复合或与带有适当抗原的gp120或gp140复合。 表位将有一个持续的努力，沟通的信封构象变化的复杂性，通过开发一个互动的分子动画，结合新的结构数据，因为它们出现。