Coronavirus Spike-RBD Variants Differentially Bind to the Human ACE2 Receptor.
Coronavirus Spike-RBD Variants Differentially Bind to the Human ACE2 Receptor.
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冠状病毒刺突-RBD 变体与人类 ACE2 受体的结合存在差异。
DOI：
10.1101/2024.03.07.583944
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Feinstein,Paul
中科院分区：
文献类型：
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作者：
Feinstein,Paul
SARS-CoV-2β冠状病毒通过与人血管紧张素受体2(ACE2)结合，然后利用跨膜蛋白酶、丝氨酸2(TMPRSS2)和Furin辅助因子输入细胞，从而感染人。对SARS-CoV-2胞外刺突蛋白的分析表明，在197个残基部分，即受体结合域(RBD)内，结合所需的关键氨基酸。膜系RBD-GFP融合蛋白和膜结合的ACE2-Cherry融合蛋白之间的基于细胞的检测允许RBD和ACE2蛋白的突变交叉。数据显示，Omicron BA.1和BA.2变体改变了对ACE2蛋白氨基末端的依赖性，表明这两种蛋白上的多个表位稳定了它们在ACE2的NT和内部区域的相互作用。相反，H-CoV-NL63 RBD只依赖于ACE2内部区域的结合。到目前为止，针对这个内部区域的肽抑制剂方法未能阻止RBDS与ACE2的结合，这表明ACE2上的几个结合区域足以允许功能相互作用。总而言之，ACE2的RBD结合表面看起来相对流畅，可以结合一系列新的变体。
The SARS-CoV-2 betacoronavirus infects people through binding the human Angiotensin Receptor 2 (ACE2), followed by import into a cell utilizing the Transmembrane Protease, Serine 2 (TMPRSS2) and Furin cofactors. Analysis of the SARS-CoV-2 extracellular spike protein has suggested critical amino acids necessary for binding within a 197-residue portion, the receptor binding domain (RBD). A cell-based assay between a membrane tethered RBD-GFP fusion protein and the membrane bound ACE2-Cherry fusion protein allowed for mutational intersection of both RBD and ACE2 proteins. Data shows Omicron BA.1 and BA.2 variants have altered dependency on the amino terminus of ACE2 protein and suggests multiple epitopes on both proteins stabilize their interactions at the Nt and internal region of ACE2. In contrast, the H-CoV-NL63 RBD is only dependent on the ACE2 internal region for binding. A peptide inhibitor approach to this internal region thus far have failed to block binding of RBDs to ACE2, suggesting that several binding regions on ACE2 are sufficient to allow functional interactions. In sum, the RBD binding surface of ACE2 appears relatively fluid and amenable to bind a range of novel variants.