Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
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DOI：
10.1126/science.abd3255
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发表时间：
2020-11-06
期刊：
影响因子：
--
通讯作者：
Schaffitzel C
中科院分区：
文献类型：
--
作者：
Toelzer C;Gupta K;Yadav SKN;Borucu U;Davidson AD;Kavanagh Williamson M;Shoemark DK;Garzoni F;Staufer O;Milligan R;Capin J;Mulholland AJ;Spatz J;Fitzgerald D;Berger I;Schaffitzel C
针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的许多开发疗法的努力集中在与宿主受体结合的刺突（S）蛋白三聚体上。三聚体S蛋白的结构显示其受体结合结构域处于向上或向下构象。Toelzer等人在昆虫细胞中产生SARS-CoV-2 S，并通过冷冻电子显微镜确定结构。在他们的数据集中，封闭形式占主导地位，并通过结合亚油酸（一种必需脂肪酸）来稳定。类似的结合口袋似乎存在于以前的高致病性冠状病毒中，过去的研究表明病毒感染与脂肪酸代谢之间存在联系。该口袋可用于开发将S蛋白捕获在闭合构象中的抑制剂。SARS-CoV-2刺突与亚油酸结合，亚油酸是炎症、免疫调节和膜流动性的关键分子。2019冠状病毒病（COVID-19）由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起，代表着一场全球危机。SARS-CoV-2治疗开发的关键是揭示驱动高感染性，广泛组织嗜性和严重病理学的机制。我们的2.85埃低温电子显微镜结构的SARS-CoV-2刺突（S）糖蛋白显示，受体结合结构域紧密结合必需的游离脂肪酸亚油酸（LA）在三个复合结合口袋。高致病性严重急性呼吸综合征冠状病毒（SARS-CoV）和中东呼吸综合征冠状病毒（MERS-CoV）似乎也存在类似的口袋。LA结合稳定了锁定的S构象，导致体外血管紧张素转换酶2（ACE 2）相互作用减少。在人类细胞中，LA补充剂与COVID-19药物remdesivir协同作用，抑制SARS-CoV-2复制。我们的结构直接连接LA和S，为SARS-CoV-2靶向LA结合的干预策略奠定了基础。
Many efforts to develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are focused on the spike (S) protein trimer that binds to the host receptor. Structures of trimeric S protein show its receptor-binding domain in either an up or a down conformation. Toelzer et al. produced SARS-CoV-2 S in insect cells and determined the structure by cryo–electron microscopy. In their dataset, the closed form was predominant and was stabilized by binding linoleic acid, an essential fatty acid. A similar binding pocket appears to be present in previous highly pathogenic coronaviruses, and past studies suggested links between viral infection and fatty acid metabolism. The pocket could be exploited to develop inhibitors that trap S protein in the closed conformation. Science, this issue p. 725 The SARS-CoV-2 spike binds linoleic acid, a key molecule in inflammation, immune modulation, and membrane fluidity. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms that drive high infectivity, broad tissue tropism, and severe pathology. Our 2.85-angstrom cryo–electron microscopy structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains tightly bind the essential free fatty acid linoleic acid (LA) in three composite binding pockets. A similar pocket also appears to be present in the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). LA binding stabilizes a locked S conformation, resulting in reduced angiotensin-converting enzyme 2 (ACE2) interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies that target LA binding by SARS-CoV-2.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
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Yamauchi Y
影响因子：
48
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Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
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Fraser JS
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
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Chen, Bing
DOI：
10.1007/978-1-4939-2272-7_12
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Fairhead, Michael;Howarth, Mark
通讯作者：
Howarth, Mark
影响因子：
6.3
作者：
BERENDSEN, HJC;VANDERSPOEL, D;VANDRUNEN, R
通讯作者：
VANDRUNEN, R