Structural Insights into the Cofactor Role of Heparin/Heparan Sulfate in Binding between the SARS-CoV-2 Spike Protein and Host Angiotensin-Converting Enzyme II
Structural Insights into the Cofactor Role of Heparin/Heparan Sulfate in Binding between the SARS-CoV-2 Spike Protein and Host Angiotensin-Converting Enzyme II
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肝素/硫酸乙酰肝素在 SARS-CoV-2 刺突蛋白与宿主血管紧张素转换酶 II 结合中的辅因子作用的结构见解
DOI：
10.1021/acs.jcim.1c01484
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发表时间：
2022-01
影响因子：
5.6
通讯作者：
Jun Gao
中科院分区：
文献类型：
--
作者：
Xiaocong Wang;Lihua Bie;Jun Gao
新型严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的病毒进入过程需要来自细胞表面的肝素和硫酸乙酰肝素，其作为人血管紧张素转换酶2（ACE 2）的辅因子，用于识别病毒粒子表面上刺突（S）蛋白的受体结合结构域（RBD）。在本研究中，在分子动力学（MD）模拟中采用Vina-Carb预测的RBD结合位点中具有四个GlcNS 6S-IdoA 2S（octa）重复单元的寡糖的结合位姿，为研究辅因子机制提供原子细节。MD模拟中的分子模型再现了从微阵列实验中观察到的长度和序列依赖性行为，并揭示了HP/HS与RBD结合的重要平面U形转弯形状。在ACE 2-RBD复合物中具有这种形状的octa模型增强了结合界面中的相互作用。与ACE 2-RBD复合物的比较表明，RBD结合位点中octa的存在阻断了RBD结合界面远端的环区域中的运动，并促进了该环区域与ACE 2 N-末端螺旋的接触。这项研究揭示了HP/HS与RBD相互作用的原子和动力学细节，并提供了它们在ACE 2-RBD相互作用中的辅助因子作用的见解。
The viral entry process of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires heparin and heparan sulfates from the cell surface, functioning as a cofactor for human angiotensin-converting enzyme 2 (ACE2) for recognizing the receptor-binding domain (RBD) of the spike (S) protein on the surface of the virion. In the present study, the binding poses of an oligosaccharide with four repeating units of GlcNS6S-IdoA2S (octa) predicted by Vina-Carb in the RBD binding site were employed in molecular dynamics (MD) simulations to provide atomic details for studying the cofactor mechanism. The molecular model in the MD simulations reproduced the length- and sequence-dependent behavior observed from the microarray experiments and revealed an important planar U-turn shape for HP/HS binding to RBD. The model for octa with this shape in the ACE2–RBD complex enhanced the interactions in the binding interface. The comparisons with the ACE2–RBD complex suggested that the presence of octa in the RBD binding site blocked the movements in a loop region at the distal end of the RBD binding interface and promoted the contacts of this loop region with the ACE2 N-terminus helix. This study shed light on the atomic and dynamic details for HP/HS interacting with RBD and provided insights into their cofactor role in the ACE2–RBD interactions.
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影响因子：
64.5
作者：
Clausen, Thomas Mandel;Sandoval, Daniel R.;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
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Walker, Ross C.
影响因子：
3.4
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影响因子：
1.1
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Singh A;Tessier MB;Pederson K;Wang X;Venot AP;Boons GJ;Prestegard JH;Woods RJ
通讯作者：
Woods RJ
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.