CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
mBio. 2024 Sep 11;15(9):e0140424. doi: 10.1128/mbio.01404-24. Epub 2024 Jul 31.
Two different sarbecoviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, have caused serious challenges to public health. Certain sarbecoviruses utilize angiotensin-converting enzyme 2 (ACE2) as their cellular receptor, whereas some do not, speculatively due to the two deletions in their receptor-binding domain (RBD). However, it remains unclear whether sarbecoviruses with one deletion in the RBD can still bind to ACE2. Here, we showed that two phylogenetically related sarbecoviruses with one deletion, BtKY72 and BM48-31, displayed a different ACE2-usage range. The cryo-electron microscopy structure of BtKY72 RBD bound to bat ACE2 identified a key residue important for the interaction between RBD and ACE2. In addition, we demonstrated that the mutations involving four types of core residues enabled the sarbecoviruses with deletion(s) to bind to human ACE2 (hACE2) and broadened the ACE2 usage of SARS-CoV-2. Our findings help predict the potential hACE2-binding ability to emerge sarbecoviruses and develop pan-sarbecovirus therapeutic agents.
Many sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), possess the ability to bind to receptor angiotensin-converting enzyme 2 (ACE2) through their receptor-binding domain (RBD). However, certain sarbecoviruses with deletion(s) in the RBD lack this capability. In this study, we investigated two closely related short-deletion sarbecoviruses, BtKY72 and BM48-31, and revealed that BtKY72 exhibited a broader ACE2-binding spectrum compared to BM48-31. Structural analysis of the BtKY72 RBD-bat ACE2 complex identifies a critical residue at position 493 contributing to these differences. Furthermore, we demonstrated that the mutations involving four core residues in the RBD enabled the sarbecoviruses with deletion(s) to bind to human ACE2 and expanded the ACE2 usage spectra of SARS-CoV-2. These findings offer crucial insights for accurately predicting the potential threat of newly emerging sarbecoviruses to human health.
两种不同的沙贝病毒，严重急性呼吸综合征冠状病毒（SARS-CoV）和 SARS-CoV-2，对公共卫生造成了严重挑战。某些沙贝病毒利用血管紧张素转换酶 2（ACE2）作为其细胞受体，而有些则不利用，推测是由于其受体结合域（RBD）中的两个缺失。然而，目前尚不清楚 RBD 中有一个缺失的沙贝病毒是否仍能与 ACE2 结合。在这里，我们表明，两种具有 RBD 一个缺失的系统发育上相关的沙贝病毒，BtKY72 和 BM48-31，显示出不同的 ACE2 利用范围。与蝙蝠 ACE2 结合的 BtKY72 RBD 的低温电子显微镜结构确定了一个关键残基，该残基对 RBD 和 ACE2 之间的相互作用很重要。此外，我们证明涉及四种核心残基的突变使具有缺失的沙贝病毒能够与人类 ACE2（hACE2）结合，并拓宽了 SARS-CoV-2 的 ACE2 利用范围。我们的研究结果有助于预测可能出现的与 hACE2 结合的沙贝病毒，并开发泛沙贝病毒治疗药物。
许多沙贝病毒，包括严重急性呼吸综合征冠状病毒 2（SARS-CoV-2），通过其受体结合域（RBD）具有与受体血管紧张素转换酶 2（ACE2）结合的能力。然而，某些 RBD 中有缺失的沙贝病毒缺乏这种能力。在这项研究中，我们研究了两种密切相关的短缺失沙贝病毒，BtKY72 和 BM48-31，并揭示 BtKY72 与 BM48-31 相比表现出更广泛的 ACE2 结合谱。BtKY72 RBD-蝙蝠 ACE2 复合物的结构分析确定了位置 493 处的一个关键残基对这些差异有贡献。此外，我们证明 RBD 中涉及四个核心残基的突变使具有缺失的沙贝病毒能够与人类 ACE2 结合，并扩大了 SARS-CoV-2 的 ACE2 利用谱。这些发现为准确预测新出现的沙贝病毒对人类健康的潜在威胁提供了重要的见解。
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