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研究系统性揭示SARS-CoV-2受体结合结构域突变的影响
作者:小柯机器人 发布时间:2020/8/13 21:18:24

近日,美国华盛顿大学Jesse D. Bloom及其研究组通过对SARS-CoV-2受体结合结构域的深度突变筛选,揭示出蛋白折叠和ACE2结合的限制区域。2020年8月11日,《细胞》杂志在线发表了这项成果。

研究人员测量了受体结合域(RBD)的所有氨基酸突变如何影响折叠蛋白的表达及其对ACE2的亲和力。大多数突变对RBD的表达和ACE2的结合都是有害的,而且研究人员在RBD的表面上发现了限制区域,这些区域可能是疫苗和抗体的理想靶标。但是,相当多的突变被很好地耐受甚至增强了ACE2结合,包括在SARS相关冠状病毒之间变化的ACE2接口残基。
 
但是,研究人员发现没有证据表明这些ACE2亲和力增强突变已在当前的SARS-CoV-2大流行分离毒株中产生选择。研究人员提出了一个交互式的可视化和开放分析渠道,能够促进这一数据集用于疫苗设计和病毒监测过程中观察到的突变功能注释。
 
据介绍,SARS-CoV-2突刺糖蛋白的受体结合域(RBD)介导病毒与ACE2受体的结合,是宿主范围的主要决定因素和中和抗体的主要靶标。
 
附:英文原文

Title: Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

Author: Tyler N. Starr, Allison J. Greaney, Sarah K. Hilton, Daniel Ellis, Katharine H.D. Crawford, Adam S. Dingens, Mary Jane Navarro, John E. Bowen, M. Alejandra Tortorici, Alexandra C. Walls, Neil P. King, David Veesler, Jesse D. Bloom

Issue&Volume: 2020-08-11

Abstract: The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.

DOI: 10.1016/j.cell.2020.08.012

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31003-5

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/