Locking down the SARS-CoV-2 spike 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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SARS-CoV-2刺突蛋白锁定结构中的游离脂肪酸结合口袋

锁定 SARS-CoV-2 尖峰 开发针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的疗法的许多努力都集中在与宿主受体结合的尖峰 (S) 蛋白三聚体上。三聚体 S 蛋白的结构显示其受体结合域呈向上或向下构象。托尔泽等人。在昆虫细胞中产生 SARS-CoV-2 S 并通过冷冻电子显微镜确定其结构。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。在以前的高致病性冠状病毒中似乎存在类似的结合口袋，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。科学，这个问题 p。725 SARS-CoV-2 尖峰与亚油酸结合，亚油酸是炎症、免疫调节和膜流动性的关键分子。由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的 2019 年冠状病毒病 (COVID-19) 是一场全球危机。SARS-CoV-2 治疗发展的关键是解开驱动高传染性、广泛组织嗜性和严重病理的机制。我们的 SARS-CoV-2 尖峰 (S) 糖蛋白的 2.85 埃低温电子显微镜结构显示，受体结合域与三个复合结合口袋中的必需游离脂肪酸亚油酸 (LA) 紧密结合。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) 中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 (ACE2) 相互作用减少。在人体细胞中，LA 补充剂与 COVID-19 药物瑞德西韦协同作用，抑制 SARS-CoV-2 复制。我们的结构直接将 LA 和 S 联系起来，为针对 SARS-CoV-2 与 LA 结合的干预策略奠定了基础。