A glycan gate controls opening of the SARS-CoV-2 spike protein.
A glycan gate controls opening of the SARS-CoV-2 spike protein.
复制标题
DOI：
10.1038/s41557-021-00758-3
复制
发表时间：
2021-10
期刊：
影响因子：
21.8
通讯作者：
Amaro RE
中科院分区：
文献类型：
--
作者：
Sztain T;Ahn SH;Bogetti AT;Casalino L;Goldsmith JA;Seitz E;McCool RS;Kearns FL;Acosta-Reyes F;Maji S;Mashayekhi G;McCammon JA;Ourmazd A;Frank J;McLellan JS;Chong LT;Amaro RE
SARS-CoV-2的感染是由刺突蛋白受体结合域（RBD）的开放控制的，其从聚糖屏蔽的“向下”状态转变为暴露的“向上”状态，以结合人ACE 2受体并感染细胞。虽然已经通过cryoEM和cryoET获得了“向上”和“向下”状态的快照，但RBD开放过渡的细节回避了实验表征。在这里，超过130 μs的完全糖基化刺突胞外域的加权系综（WE）模拟使我们能够表征300多个连续的、动力学无偏的RBD开放途径。连同冷冻EM数据和生物层干涉实验的ManifoldEM分析，我们揭示了在位置N343的N-聚糖的门控作用，这有利于RBD开放。残基D405、R408和D427也参与。本文提供的糖基化刺突激活机制的原子水平表征实现了系综途径模拟的新的高水位标记，并为理解SARS-CoV-2病毒进入和感染的基本机制提供了基础。
SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded “down” to an exposed “up” state in order to bind the human ACE2 receptor and infect cells. While snapshots of the “up” and “down” states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Together with ManifoldEM analysis of cryo-EM data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408, and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.
登录
查看更多内容
影响因子：
5.5
作者：
Suarez, Ernesto;Lettieri, Steven;Zwier, Matthew C.;Stringer, Carsen A.;Subramanian, Sundar Raman;Chong, Lillian T.;Zuckerman, Daniel M.
通讯作者：
Zuckerman, Daniel M.
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
影响因子：
168.9
作者：
Chan, Jasper Fuk-Woo;Yuan, Shuofeng;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
影响因子：
16.8
作者：
Henderson R;Edwards RJ;Mansouri K;Janowska K;Stalls V;Gobeil SMC;Kopp M;Li D;Parks R;Hsu AL;Borgnia MJ;Haynes BF;Acharya P
通讯作者：
Acharya P
DOI：
10.1073/pnas.1419276111
发表时间：
2014-12-09
影响因子：
11.1
作者：
Dashti, Ali;Schwander, Peter;Ourmazd, Abbas
通讯作者：
Ourmazd, Abbas