RAPID: Structural investigation of interactors of SARS CoV 2

RAPID：SARS CoV 2 相互作用因子的结构研究

• 批准号: 2031205
• 负责人: James Fraser
• 金额: $ 20万
• 依托单位: University of California-San Francisco
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031205&HistoricalAwards=false
• 关键词: RAPID; Structural; investigation; interactors; SARS

The SARS-COV-2 virus genome encodes a very small set of proteins. Having such a minimal genome means that the virus relies on host factors to complete its infectious cycle. Researchers supported by this award will investigate the mechanisms by which interactions between viral and host cell proteins might antagonize innate immune defenses and lead to increased virulence. Elucidating the structural basis for how SARS-COV-2 hijacks and disrupts host cellular processes may aid in the development of host-directed therapies as a means to combat epidemics and will provide new insight into how genetic variation of host proteins can influences differences in infection severity and spread between populations and species. Data and resources from these studies will be rapidly disseminated through public WWW-sites, social media, shared data repositories, and published in peer-reviewed scientific journals.Protein regions that are structurally dynamic upon changing the data collection temperature are highly correlated with small molecule binding sites. Studies supported by this award will test the hypothesis that the regions of viral and host proteins that are most structurally susceptible to temperature perturbation, detectable by multi-temperature synchrotron and x-ray free electron laser (XFEL) experiments, are likely to represent the footprints of protein-protein interactions and to bind small molecule ligands. The researchers will use an innovative combination of multi-temperature X-ray data collection of individual proteins at synchrotrons and XFELs, high throughput crystal fragment screening, and structure determination of viral-human complexes. Results from these studies will advance the understanding of SARS-COV-2 biology and may also yield more generalizable insights into mechanisms of virulence. This RAPID award to the University of California-San Francisco is made by the Division of Biological Infrastructure using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

SARS-COV-2病毒基因组编码一组非常小的蛋白质。拥有这样一个最小的基因组意味着病毒依赖于宿主因素来完成其感染周期。 该奖项支持的研究人员将研究病毒和宿主细胞蛋白之间的相互作用可能拮抗先天免疫防御并导致毒力增加的机制。阐明SARS-COV-2如何劫持和破坏宿主细胞过程的结构基础可能有助于开发宿主导向疗法作为对抗流行病的手段，并将为宿主蛋白质的遗传变异如何影响感染严重程度的差异以及种群和物种之间的传播提供新的见解。 来自这些研究的数据和资源将通过公共WWW网站、社交媒体、共享数据库迅速传播，并发表在同行评议的科学期刊上。在改变数据收集温度时结构动态的蛋白质区域与小分子结合位点高度相关。该奖项支持的研究将测试以下假设：病毒和宿主蛋白质的结构最容易受到温度扰动的区域，可通过多温度同步加速器和X射线自由电子激光（XFEL）实验检测，可能代表蛋白质-蛋白质相互作用的足迹并结合小分子配体。研究人员将使用同步加速器和XFEL的单个蛋白质的多温度X射线数据收集，高通量晶体片段筛选以及病毒-人类复合物的结构测定的创新组合。这些研究的结果将促进对SARS-COV-2生物学的理解，也可能对毒力机制产生更普遍的见解。 加州大学弗朗西斯科分校的RAPID奖项由生物基础设施部使用冠状病毒援助，救济和经济安全（CARES）法案的资金颁发。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。