Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
J Mol Biol. 2021 Jul 23;433(15):167058. doi: 10.1016/j.jmb.2021.167058. Epub 2021 May 21.
Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 7-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation only slightly enhances the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 2-fold weaker than N501Y. However, the recently emerging double mutant E484K/N501Y binds even stronger than N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.
SARS-CoV-2 的迅速传播的新变种在病毒刺突蛋白上携带多个突变，这些突变附着在宿主细胞上的血管紧张素转化酶 2（ACE2）受体上。这些突变包括氨基酸变化 N501Y（谱系 B.1.1.7，首先在英国发现）和 N501Y、E484K、K417N 的组合（B.1.351，首先在南非发现），都位于受体结合域（RBD）的界面上。我们通过实验证实，含有 N501Y 突变的 RBD 与 hACE2 受体的结合强度比野生型 RBD 强 7 倍。E484K 突变仅略微增强了与受体的亲和力，而 K417N 则降低了亲和力。因此，含有所有三种突变的 B.1.351 的 RBD 与 hACE2 的结合强度比野生型 RBD 强 3 倍，但比 N501Y 弱 2 倍。然而，最近出现的 E484K/N501Y 双突变体的结合强度甚至比 N501Y 更强。含有对受体结合亲和力、病毒传播和免疫逃避有不同影响的突变的谱系的独立进化，突显了全球病毒基因组监测和功能特征分析的重要性。
