A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
复制标题
DOI：
10.1016/j.bpj.2021.01.037
复制
发表时间：
2021-03-16
影响因子：
3.4
通讯作者：
Mulholland AJ
中科院分区：
文献类型：
--
作者：
Oliveira ASF;Ibarra AA;Bermudez I;Casalino L;Gaieb Z;Shoemark DK;Gallagher T;Sessions RB;Amaro RE;Mulholland AJ
Changeux等人（Changeux et al. C. R. 343：33-39）。最近提出SARS-CoV-2刺突蛋白可能与烟碱乙酰胆碱受体（nAChR）相互作用，并且这种相互作用可能涉及病理学和感染性。这一假设是基于SARS-CoV-2刺突蛋白含有与已知nAChR拮抗剂相似的序列基序的事实。在这里，我们使用分子模拟验证的原子详细结构的nAChRs和穗调查可能的结合的Y674-R685区域的穗nAChRs。我们研究了Y674-R685环与三种nAChR的结合，即人α4β2和α7亚型以及来自Tetronarce californica的肌肉样αβγδ受体。我们的结果预测Y674-R685对nAChR具有亲和力。负责结合的刺突区域包含PRRA基序，这是一种在其他SARS样冠状病毒中未发现的四个残基插入。结合Y674-R685的构象行为高度依赖于受体亚型;它在α4β2和α7复合物中采用扩展构象，但在与肌肉样受体结合时更紧凑。在α4β2和αβγδ复合物中，Y674-R685与受体的相互作用迫使环C区采取开放构象，类似于其他已知的nAChR拮抗剂。相比之下，在α7复合物中，Y674-R685深入渗透到结合口袋中，在那里它与芳香盒内衬的残基，即TrpB，TyrC 1和TyrC 2形成相互作用。结合能的估计表明，Y674-R685与所有三种nAChR亚型形成稳定的复合物。糖基化刺突的模拟分析显示Y674-R685区域可用于结合。我们建议一个潜在的结合方向的刺突蛋白与nAChRs，其中它们是在一个非平行的安排彼此。
Changeux et al. (Changeux et al. C. R. Biol. 343:33–39.) recently suggested that the SARS-CoV-2 spike protein may interact with nicotinic acetylcholine receptors (nAChRs) and that such interactions may be involved in pathology and infectivity. This hypothesis is based on the fact that the SARS-CoV-2 spike protein contains a sequence motif similar to known nAChR antagonists. Here, we use molecular simulations of validated atomically detailed structures of nAChRs and of the spike to investigate the possible binding of the Y674-R685 region of the spike to nAChRs. We examine the binding of the Y674-R685 loop to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγδ receptor from Tetronarce californica. Our results predict that Y674-R685 has affinity for nAChRs. The region of the spike responsible for binding contains a PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. The conformational behavior of the bound Y674-R685 is highly dependent on the receptor subtype; it adopts extended conformations in the α4β2 and α7 complexes but is more compact when bound to the muscle-like receptor. In the α4β2 and αβγδ complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation, similar to other known nAChR antagonists. In contrast, in the α7 complex, Y674-R685 penetrates deeply into the binding pocket in which it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1, and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of simulations of the glycosylated spike show that the Y674-R685 region is accessible for binding. We suggest a potential binding orientation of the spike protein with nAChRs, in which they are in a nonparallel arrangement to one another.
登录
查看更多内容
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
通讯作者：
Yamauchi Y
超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
影响因子：
18.2
作者：
Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
通讯作者：
Amaro RE
影响因子：
5
作者：
Baig, Abdul Mannan;Sanders, Erin C.
通讯作者：
Sanders, Erin C.
影响因子：
23.5
作者：
Campello, Hugo Rego;Del Villar, Silvia G.;Gallagher, Timothy
通讯作者：
Gallagher, Timothy
影响因子：
3.4
作者：
Apellániz B;Huarte N;Largo E;Nieva JL
通讯作者：
Nieva JL