SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy.
SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy.
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作者：
Yang Z;Han Y;Ding S;Shi W;Zhou T;Finzi A;Kwong PD;Mothes W;Lu M
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）变异体（VOC）在刺突（S）糖蛋白中存在突变，这些突变可提高传播效率，并降低COVID-19疫苗和抗体疗法的疗效。S介导病毒进入，是抗体应答的主要靶点，可溶性S变体的结构研究揭示了人血管紧张素转换酶2（hACE 2）受体可接近的构象倾向增加。然而，一直缺乏实时观察的构象动力学的结构平衡的S变体。在这里，我们报告了单分子Förster共振能量转移（smFRET）研究，在病毒颗粒的背景下，在VOCs中观察到的关键突变，包括D 614 G和E484 K。调查的变体主要占据更开放的hACE 2可访问的构象，同意与以前的可溶性三聚体的结构。此外，这些S变体在hACE 2可接近/结合状态中表现出较慢的转变。我们的发现增加S动力学稳定性的开放构象提供了一个新的视角SARS-CoV-2适应人群。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) harbor mutations in the spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses, with structural studies of soluble S variants revealing an increased propensity toward conformations accessible to the human angiotensin-converting enzyme 2 (hACE2) receptor. However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster resonance energy transfer (smFRET) studies of critical mutations observed in VOCs, including D614G and E484K, in the context of virus particles. Investigated variants predominately occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited slower transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population.
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