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对SARS-CoV-2受体结合域的深度突变扫描显示了折叠和ACE2结合的限制
Tyler N Starr1, Allison J Greaney2, Sarah K Hilton3
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell
|August 26, 2020
概括
研究了SARS-CoV-2尖端蛋白的受体结合域 (RBD) 的突变. 大多数突变会损害蛋白质表达和ACE2结合,但有些突变会增强蛋白质表达,尽管它们尚未在流行性菌株中被选择.
科学领域:
- 病毒学
- 免疫学
- 结构生物学
背景情况:
- 通过ACE2受体结合,SARS-CoV-2尖端蛋白的受体结合域 (RBD) 对于病毒进入至关重要.
- RBD是中和抗体的主要目标,并影响宿主范围.
- 了解突变对RBD功能的影响对于治疗和疫苗开发至关重要.
研究的目的:
- 通过实验评估SARS-CoV-2 RBD中所有可能的氨基酸突变对蛋白质表达和ACE2结合性的影响.
- 在RBD中确定关键的功能和潜在的干预目标.
- 调查正在进行的流行病期间是否选择了增强ACE2结合的突变.
主要方法:
- SARS-CoV-2 RBD 的系统性突变.
- 对折叠蛋白的表达水平进行实验测量.
- 用于量化与人类ACE2受体的结合亲和力.
- 生物信息分析和交互式数据可视化
主要成果:
- 大多数氨基酸突变会对RBD表达和ACE2结合产生负面影响.
- 在RBD表面特定的受限制区域被确定为潜在的脆弱目标.
- 发现一小部分突变能够很好地耐受或增强ACE2结合,包括在与SARS相关的冠状病毒中保存的残留物.
- 在目前的SARS-CoV-2大流行分离物中没有发现ACE2亲和力增强突变的证据.
结论:
- 大多数RBD突变是有害的,这表明通过改变ACE2结合的免疫规避的进化途径有限.
- 在RBD上受限制的地区为持久疫苗和抗体疗法提供了有希望的目标.
- 数据集和分析管道为持续的SARS-CoV-2监测和治疗设计提供了宝贵的资源.
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