Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
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DOI：
10.1016/j.cell.2020.09.032
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发表时间：
2020-10-29
期刊：
影响因子：
64.5
通讯作者：
Luban, Jeremy
中科院分区：
文献类型：
--
作者：
Yurkovetskiy, Leonid;Wang, Xue;Luban, Jeremy
SARS-CoV-2刺突（S）蛋白变体D 614 G在世界范围内取代了祖先病毒，在几个月内接近固定。在这里，我们表明，D 614 G是更具感染性的祖先的形式，对人类肺细胞，结肠细胞，并在细胞上提供允许的异位表达的人ACE 2或ACE 2的直系同源物从各种哺乳动物，包括中国棕褐色的马蹄蝙蝠和马来穿山甲。D 614 G没有改变S蛋白的合成、加工或掺入SARS-CoV-2颗粒，但由于更快的解离速率，D 614 G对ACE 2的亲和力降低。通过冷冻电子显微镜对S蛋白三聚体的评估表明，D 614 G破坏了原聚体间的接触，并且构象向ACE 2结合活性状态转变，该状态被建模为病毒体膜与靶细胞融合的途径。与这种更开放的构象一致，靶向S蛋白受体结合结构域的抗体的中和效力并未减弱。
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.