Bioinformatics and Molecular Medicine Research Group, Dow Research Institute of Biotechnology and Biomedical Sciences, Dow College of Biotechnology, Dow University of Health Sciences, Karachi, Pakistan.
Department of Microbiology, University of Karachi, Karachi, Pakistan.
J Med Virol. 2020 Sep;92(9):1580-1586. doi: 10.1002/jmv.25832. Epub 2020 Apr 15.
The recent pandemic of COVID-19, caused by SARS-CoV-2, is unarguably the most fearsome compared with the earlier outbreaks caused by other coronaviruses, SARS-CoV and MERS-CoV. Human ACE2 is now established as a receptor for the SARS-CoV-2 spike protein. Where variations in the viral spike protein, in turn, lead to the cross-species transmission of the virus, genetic variations in the host receptor ACE2 may also contribute to the susceptibility and/or resistance against the viral infection. This study aims to explore the binding of the proteins encoded by different human ACE2 allelic variants with SARS-CoV-2 spike protein. Briefly, coding variants of ACE2 corresponding to the reported binding sites for its attachment with coronavirus spike protein were selected and molecular models of these variants were constructed by homology modeling. The models were then superimposed over the native ACE2 and ACE2-spike protein complex, to observe structural changes in the ACE2 variants and their intermolecular interactions with SARS-CoV-2 spike protein, respectively. Despite strong overall structural similarities, the spatial orientation of the key interacting residues varies in the ACE2 variants compared with the wild-type molecule. Most ACE2 variants showed a similar binding affinity for SARS-CoV-2 spike protein as observed in the complex structure of wild-type ACE2 and SARS-CoV-2 spike protein. However, ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein. In summary, our data provide a structural basis of potential resistance against SARS-CoV-2 infection driven by ACE2 allelic variants.
最近由 SARS-CoV-2 引起的 COVID-19 大流行无疑是与之前由 SARS-CoV 和 MERS-CoV 引起的冠状病毒爆发相比最可怕的一次。人类 ACE2 现在被确定为 SARS-CoV-2 刺突蛋白的受体。病毒刺突蛋白的变异导致病毒的跨物种传播，而宿主受体 ACE2 的遗传变异也可能导致对病毒感染的易感性和/或抵抗力。本研究旨在探索不同人类 ACE2 等位基因变异体编码的蛋白质与 SARS-CoV-2 刺突蛋白的结合。简而言之，选择了与冠状病毒刺突蛋白附着的 ACE2 报告结合位点相对应的 ACE2 编码变异体，并通过同源建模构建了这些变异体的分子模型。然后将模型叠加在天然 ACE2 和 ACE2-刺突蛋白复合物上，分别观察 ACE2 变异体的结构变化及其与 SARS-CoV-2 刺突蛋白的分子间相互作用。尽管具有很强的整体结构相似性，但 ACE2 变异体中关键相互作用残基的空间取向与野生型分子相比有所不同。与野生型 ACE2 和 SARS-CoV-2 刺突蛋白复合物结构观察到的情况相比，大多数 ACE2 变异体对 SARS-CoV-2 刺突蛋白表现出相似的结合亲和力。然而，ACE2 等位基因 rs73635825（S19P）和 rs143936283（E329G）在与病毒刺突蛋白的分子间相互作用方面表现出明显的差异。总之，我们的数据为 ACE2 等位基因变异体驱动的对 SARS-CoV-2 感染的潜在抵抗力提供了结构基础。
