Effects of common mutations in the SARS-CoV-2 Spike RBD domain and its ligand the human ACE2 receptor on binding affinity and kinetics
Effects of common mutations in the SARS-CoV-2 Spike RBD domain and its ligand the human ACE2 receptor on binding affinity and kinetics
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DOI：
10.1101/2021.05.18.444646
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发表时间：
2021-05
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通讯作者：
Michael I. MacGowan;Stuart Kutuzov;Mikhail Dushek;O. Barton;Geoffrey J. Merwe;P. Anton;Michael I. Barton;Stuart A. MacGowan;M. Kutuzov;Omer Dushek;G. Barton;A. V. D. Merwe
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作者：
Michael I. MacGowan;Stuart Kutuzov;Mikhail Dushek;O. Barton;Geoffrey J. Merwe;P. Anton;Michael I. Barton;Stuart A. MacGowan;M. Kutuzov;Omer Dushek;G. Barton;A. V. D. Merwe
SARS-CoV-2病毒刺突蛋白受体结合域(RBD)与ACE2细胞表面蛋白的相互作用是病毒感染细胞所必需的。RBD结构域的突变存在于全世界独立出现的令人担忧的SARS-CoV-2变种中。例如，传播性更强的B.1.1.7谱系在其Spike RBD结构域中有一个突变(N501Y)，该突变增强了与ACE2的结合。在RBD结合位点突变的人类中也存在ACE2等位基因。在这里，我们对五个常见的RBD突变(K417N、K417T、N501Y、E484K和S477N)和两个常见的ACE2突变(S19P和K26R)对RBD/ACE2相互作用的影响进行了详细的亲和力和动力学分析。我们分析了在英国(B.1.1.7)、南非(B.1.351)和巴西(P1)首次发现的新的SARS-CoV-2变异中发现的单个RBD突变和组合的影响。这些突变大多增加了RBD/ACE2相互作用的亲和力。K417N/T突变是个例外，它降低了亲和力。结合其他研究，我们的结果表明，N501Y和S477N突变主要促进传播，K417N/T突变促进免疫逃避，E484K突变促进传播和免疫逃避。
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD domain are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the more transmissible B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD domain that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations, and combinations found in new SARS-CoV-2 variants first identified in the UK (B.1.1.7), South Africa (B.1.351) and Brazil (P1). Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations primarily enhance transmission, the K417N/T mutations facilitate immune escape, and the E484K mutation facilitates both transmission and immune escape.