Structural Biology of Disease Processes Laboratory, NW1 1AT, London, UK.
Structural Biology Science Technology Platform, NW1 1AT, London, UK.
Nat Commun. 2022 Mar 4;13(1):1178. doi: 10.1038/s41467-022-28768-w.
Recently emerged variants of SARS-CoV-2 contain in their surface spike glycoproteins multiple substitutions associated with increased transmission and resistance to neutralising antibodies. We have examined the structure and receptor binding properties of spike proteins from the B.1.1.7 (Alpha) and B.1.351 (Beta) variants to better understand the evolution of the virus in humans. Spikes of both variants have the same mutation, N501Y, in the receptor-binding domains. This substitution confers tighter ACE2 binding, dependent on the common earlier substitution, D614G. Each variant spike has acquired other key changes in structure that likely impact virus pathogenesis. The spike from the Alpha variant is more stable against disruption upon binding ACE2 receptor than all other spikes studied. This feature is linked to the acquisition of a more basic substitution at the S1-S2 furin site (also observed for the variants of concern Delta, Kappa, and Omicron) which allows for near-complete cleavage. In the Beta variant spike, the presence of a new substitution, K417N (also observed in the Omicron variant), in combination with the D614G, stabilises a more open spike trimer, a conformation required for receptor binding. Our observations suggest ways these viruses have evolved to achieve greater transmissibility in humans.
最近出现的 SARS-CoV-2 变体在其表面刺突糖蛋白中包含多个与增加传播和对中和抗体的抗性相关的突变。我们研究了 B.1.1.7（Alpha）和 B.1.351（Beta）变体的刺突蛋白的结构和受体结合特性，以更好地了解病毒在人类中的进化。两种变体的刺突都在受体结合域具有相同的突变 N501Y。这种取代赋予了与常见的早期取代 D614G 更紧密的 ACE2 结合。每个变体的刺突在结构上都获得了其他关键的变化，这可能会影响病毒的发病机制。与研究的所有其他刺突相比，Alpha 变体的刺突在与 ACE2 受体结合时更稳定，不易被破坏。这一特性与在 S1-S2 弗林位点获得更碱性的取代（在 Delta、Kappa 和 Omicron 变体中也观察到）有关，这允许近乎完全的切割。在 Beta 变体的刺突中，新的取代 K417N（也在 Omicron 变体中观察到）的存在，与 D614G 一起，稳定了更开放的刺突三聚体，这是受体结合所必需的构象。我们的观察结果表明，这些病毒已经进化出了在人类中实现更高传染性的方式。
