Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains.
Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains.
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不含和含ACE 2的SARS-CoV-2刺突的Cryo-EM结构揭示了介导受体结合结构域的内体定位的pH依赖性开关。
DOI：
10.1016/j.chom.2020.11.004
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发表时间：
2020-12-09
影响因子：
30.3
通讯作者：
Kwong PD
中科院分区：
文献类型：
--
作者：
Zhou T;Tsybovsky Y;Gorman J;Rapp M;Cerutti G;Chuang GY;Katsamba PS;Sampson JM;Schön A;Bimela J;Boyington JC;Nazzari A;Olia AS;Shi W;Sastry M;Stephens T;Stuckey J;Teng IT;Wang P;Wang S;Zhang B;Friesner RA;Ho DD;Mascola JR;Shapiro L;Kwong PD
SARS-CoV-2刺突采用移动的受体结合结构域（RBD）来接合人ACE 2受体并促进病毒进入，这可以通过低pH内体途径发生。要了解如何ACE 2结合和低pH值影响穗构象，我们确定了冷冻电子显微镜结构在血清学和内体pH值描绘穗识别多达三个ACE 2分子。RBD自由地采用ACE 2相互作用所需的“向上”构象，主要是通过RBD运动结合邻近结构域的较小改变。在没有ACE 2的情况下，单一RBD向上构象在pH 5.5下占主导地位，在较低的pH值下分解成一个孤立的所有向下构象。值得注意的是，pH值依赖性的重折叠区域（残基824-858）在穗interdomain接口显示戏剧性的结构重排和介导的RBD定位通过协调运动的整个三聚体顶点。这些结构提供了一个基础，了解prefusion-spike机制管理内体进入，我们认为，低pH值的所有向下的构象可能有利于免疫逃避从RBD的结合抗体。确定SARS-CoV-2刺突沿着其内体进入途径的冷冻电镜结构揭示pH依赖性开关介导RBD定位的结构基础显示刺突在低pH下仅采用全RBD-向下构象建议低pH全RBD-向下构象为免疫逃避提供基础Zhou et al.确定了SARS-CoV-2刺突的12种结构，由ACE 2受体和配体自由结合，揭示了pH依赖性开关介导刺突受体结合结构域（RBD）的定位。在低pH下，刺突采用全RBD-向下构象，这提供了一种潜在的免疫逃避RBD-向上识别抗体的手段。
The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we determined cryo-electron microscopy structures—at serological and endosomal pH—delineating spike recognition of up to three ACE2 molecules. RBDs freely adopted “up” conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824–858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody. Determine cryo-EM structures of SARS-CoV-2 spike along its endosomal entry pathway Reveal structural basis by which a pH-dependent switch mediates RBD positioning Show spike to exclusively adopt an all-RBD-down conformation at low pH Suggest low-pH all-RBD-down conformation to provide a basis for immune evasion Zhou et al. determine 12 structures of the SARS-CoV-2 spike, bound by ACE2 receptor and ligand free, that reveal a pH-dependent switch to mediate positioning of spike receptor-binding domains (RBDs). At low pH, the spike adopts an all-RBD-down conformation, which provides a potential means of immune evasion from RBD-up-recognizing antibody.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K