Host Cell Membrane Capture by the SARS-CoV-2 Spike Protein Fusion Intermediate.
Host Cell Membrane Capture by the SARS-CoV-2 Spike Protein Fusion Intermediate.
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DOI：
10.1021/acscentsci.3c00158
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发表时间：
2023-06-28
影响因子：
18.2
通讯作者：
O'Shaughnessy, Ben
中科院分区：
文献类型：
--
作者：
Su, Rui;Zeng, Jin;Marcink, Tara C.;Porotto, Matteo;Moscona, Anne;O'Shaughnessy, Ben
SARS-CoV-2 进入细胞是由病毒体表面的刺突 S 蛋白的 S2 亚基捕获宿主细胞膜并与病毒包膜融合来完成的。捕获和融合需要融合前 S2 转变为其有效的融合形式，即融合中间体 (FI)。然而，FI 结构未知，无法获得 FI 的详细计算模型，并且膜捕获和融合的机制和时间尚未建立。在这里，我们通过从已知的 SARS-CoV-2 融合前和融合后结构推断，构建了 SARS-CoV-2 FI 的全长模型。在原子和粗粒度分子动力学模拟中，FI 非常灵活，并且由于 C 端碱基中的三个铰链而执行巨大的弯曲和拉伸波动。模拟的配置及其巨大波动在数量上与最近使用冷冻电子断层扫描测量的 SARS-CoV-2 FI 配置一致。模拟表明宿主细胞膜捕获时间为 ∼2 ms。分离的融合肽模拟鉴定了一个N末端螺旋，该螺旋指导并维持与膜的结合，但严重低估了结合时间，表明融合肽环境在附着到其宿主融合蛋白上时发生了根本改变。 FI 的大构型波动产生了大量的探索体积，有助于捕获目标膜，并可能设定 FI 波动触发的重折叠的等待时间，从而将病毒包膜和宿主细胞膜拉在一起进行融合。这些结果将 FI 描述为利用大量构型波动进行有效膜捕获的机器，并提出了新的潜在药物靶点。 SARS-CoV-2 释放刺突融合中间体进入细胞。模拟显示 3 个碱基铰链介导巨大的波动，从而能够在 ∼2 毫秒后捕获靶细胞，并可能触发重折叠。
Cell entry by SARS-CoV-2 is accomplished by the S2 subunit of the spike S protein on the virion surface by capture of the host cell membrane and fusion with the viral envelope. Capture and fusion require the prefusion S2 to transit to its potent fusogenic form, the fusion intermediate (FI). However, the FI structure is unknown, detailed computational models of the FI are unavailable, and the mechanisms and timing of membrane capture and fusion are not established. Here, we constructed a full-length model of the SARS-CoV-2 FI by extrapolating from known SARS-CoV-2 pre- and postfusion structures. In atomistic and coarse-grained molecular dynamics simulations the FI was remarkably flexible and executed giant bending and extensional fluctuations due to three hinges in the C-terminal base. The simulated configurations and their giant fluctuations are quantitatively consistent with SARS-CoV-2 FI configurations measured recently using cryo-electron tomography. Simulations suggested a host cell membrane capture time of ∼2 ms. Isolated fusion peptide simulations identified an N-terminal helix that directed and maintained binding to the membrane but grossly underestimated the binding time, showing that the fusion peptide environment is radically altered when attached to its host fusion protein. The large configurational fluctuations of the FI generated a substantial exploration volume that aided capture of the target membrane, and may set the waiting time for fluctuation-triggered refolding of the FI that draws the viral envelope and host cell membrane together for fusion. These results describe the FI as machinery that uses massive configurational fluctuations for efficient membrane capture and suggest novel potential drug targets. SARS-CoV-2 unleashes the spike fusion intermediate to enter cells. Simulations reveal 3 base hinges mediating giant fluctuations that enable target cell capture after ∼2 ms and may trigger refolding.
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DOI：
10.1056/nejmoa2029849
发表时间：
2021-01-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Chen P;Nirula A;Heller B;Gottlieb RL;Boscia J;Morris J;Huhn G;Cardona J;Mocherla B;Stosor V;Shawa I;Adams AC;Van Naarden J;Custer KL;Shen L;Durante M;Oakley G;Schade AE;Sabo J;Patel DR;Klekotka P;Skovronsky DM;BLAZE-1 Investigators
通讯作者：
BLAZE-1 Investigators
影响因子：
64.5
作者：
Hoffmann M;Arora P;Groß R;Seidel A;Hörnich BF;Hahn AS;Krüger N;Graichen L;Hofmann-Winkler H;Kempf A;Winkler MS;Schulz S;Jäck HM;Jahrsdörfer B;Schrezenmeier H;Müller M;Kleger A;Münch J;Pöhlmann S
通讯作者：
Pöhlmann S
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
影响因子：
3.4
作者：
Gorgun D;Lihan M;Kapoor K;Tajkhorshid E
通讯作者：
Tajkhorshid E
影响因子：
5.5
作者：
de Jong, Djurre H.;Singh, Gurpreet;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.