Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
Biochem Biophys Res Commun. 2021 Jul 12;562:89-93. doi: 10.1016/j.bbrc.2021.05.058. Epub 2021 May 21.
New SARS-CoV-2 variants emerged in the United Kingdom and South Africa in December 2020 in concomitant with the Brazillian variant in February 2021 (B.1.1.248 lineage) and currently sparking worldwide during the last few months. The new strain 501.V2 in South Africa bears three mutations in the spike receptor-binding domain (RBD); K417 N, E484K, and N501Y, while the Brazilian B.1.1.248 lineage has 12 mutations. In the current study, we simulate the complex ACE2-SARS-CoV-2 spike RBD system in which the RBD is in the wild-type and mutated isoforms. Additionally, the cell-surface Glucose Regulated Protein 78 (CS-GRP78) associated with the ACE2-SARS-CoV-2 spike RBD complex (ACE2-S RBD) is modeled at the presence of these mutant variants of the viral spike. The results showed that E484K and N501Y are critical in viral spike recognition through either ACE2 or CS-GRP78. The mutated variants (the UK, South African, and Brazilian) of the spike RBD tightly bind to GRP78 more than in the case of the wild-type RBD. These results point to the potent role of GRP78 with ACE2 in the attachment of the new variants, which could be a key for the design of inhibitors to block SARS-CoV-2 attachment and entry to the host cell.
2020 年 12 月，英国和南非出现了新的 SARS-CoV-2 变种，同时 2021 年 2 月还出现了巴西变种（B.1.1.248 谱系），最近几个月在全球范围内引发关注。南非的新菌株 501.V2 在刺突受体结合域（RBD）中有三个突变；K417N、E484K 和 N501Y，而巴西的 B.1.1.248 谱系有 12 个突变。在目前的研究中，我们模拟了 ACE2-SARS-CoV-2 刺突 RBD 系统的复杂性，其中 RBD 存在野生型和突变体两种形式。此外，与 ACE2-SARS-CoV-2 刺突 RBD 复合物（ACE2-S RBD）相关的细胞表面葡萄糖调节蛋白 78（CS-GRP78）在这些病毒刺突突变体存在的情况下也被建模。结果表明，E484K 和 N501Y 对病毒刺突的 ACE2 或 CS-GRP78 的识别至关重要。突变的变体（英国、南非和巴西）与 GRP78 的结合比野生型 RBD 更紧密。这些结果表明，GRP78 与 ACE2 在新变体的附着中起着重要作用，这可能是设计抑制剂以阻止 SARS-CoV-2 附着和进入宿主细胞的关键。
