Gao Bin, Zhu Shunyi
Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Front Microbiol. 2023 Jun 19;14:1195156. doi: 10.3389/fmicb.2023.1195156. eCollection 2023.
Peptide binders are of great interest to both basic and biomedical research due to their unique properties in manipulating protein functions in a precise spatial and temporal manner. The receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein is a ligand that captures human angiotensin-converting enzyme 2 (ACE2) to initiate infection. The development of binders of RBDs has value either as antiviral leads or as versatile tools to study the functional properties of RBDs dependent on their binding positions on the RBDs. In this study, we report two microbe-derived antibacterial defensins with RBD-binding activity. These two naturally occurring binders bind wild-type RBD (WT RBD) and RBDs from various variants with moderate-to-high affinity (7.6-1,450 nM) and act as activators that enhance the ACE2-binding activity of RBDs. Using a computational approach, we mapped an allosteric pathway in WT RBD that connects its ACE2-binding sites to other distal regions. The latter is targeted by the defensins, in which a cation-π interaction could trigger the peptide-elicited allostery in RBDs. The discovery of the two positive allosteric peptides of SARS-CoV-2 RBD will promote the development of new molecular tools for investigating the biochemical mechanisms of RBD allostery.
肽结合剂因其能够以精确的空间和时间方式操纵蛋白质功能的独特性质，在基础研究和生物医学研究中都备受关注。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的受体结合域（RBD）是一种配体，可捕获人类血管紧张素转换酶2（ACE2）以引发感染。开发RBD的结合剂作为抗病毒先导物或作为研究RBD功能特性的通用工具都具有价值，这取决于它们在RBD上的结合位置。在本研究中，我们报告了两种具有RBD结合活性的微生物来源的抗菌防御素。这两种天然存在的结合剂以中到高亲和力（7.6 - 1450 nM）结合野生型RBD（WT RBD）和来自各种变体的RBD，并作为激活剂增强RBD的ACE2结合活性。我们使用一种计算方法，在WT RBD中绘制了一条变构途径，该途径将其ACE2结合位点连接到其他远端区域。后者是防御素的作用靶点，其中阳离子-π相互作用可触发RBD中由肽引发的变构效应。SARS-CoV-2 RBD的这两种正变构肽的发现将促进用于研究RBD变构生化机制的新分子工具的开发。
