SARS-related coronavirus S-protein structures reveal synergistic RBM interactions underpinning high-affinity human ACE2 binding.

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Tác giả: Jing Chen, Xinwen Chen, Lutang Fu, Gul Habib, Jun He, Mei Li, Zexuan Li, Zimu Li, Banghui Liu, Yutong Liu, Yong Ma, Zhengli Shi, Mengzhen Su, Jingjing Wang, Peiyi Wang, Xiaoli Xiong, Hang Yuan, Peng Zhou

Ngôn ngữ: eng

Ký hiệu phân loại: 620.0045 Engineering and allied operations

Thông tin xuất bản: United States : Science advances , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 707635

High-affinity and specific binding toward the human angiotensin-converting enzyme 2 (hACE2) receptor by severe acute respiratory syndrome coronavirus (SARS)-related coronaviruses (SARSr-CoVs) remains incompletely understood. We report cryo-electron microscopy structures of eight different S-proteins from SARSr-CoVs found across Asia, Europe, and Africa. These S-proteins all adopt tightly packed, locked, prefusion conformations. These structures enable the classification of SARSr-CoV S-proteins into three types, based on their receptor-binding motif (RBM) structures and ACE2 binding characteristics. Type-2 S-proteins often preferentially bind bat ACE2 (bACE2) over hACE2. We report a structure of a type-2 BtKY72-RBD in complex with bACE2 to understand ACE2 specificity. Structure-guided mutagenesis of BtKY72-RBD reveals that multiple synergistic mutations in four different regions of RBM are required to achieve high-affinity hACE2 binding. Similar RBM changes can also confer hACE2 binding to another type-2 BM48-31 S-protein, which is primarily non-ACE2 binding. These results provide an understanding of how high-affinity hACE2 binding may be acquired by SARSr-CoV S-proteins.
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