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

• DOI: 10.1126/sciadv.adr8772
• Publication Date: 2025-03-14T17:58:26Z
• Authors: Jingjing Wang; Yong Ma; Zimu Li; Hang Yuan; Banghui Liu; Zexuan Li; Mengzhen Su; Gul Habib; Yutong Liu; Lutang Fu; Peiyi Wang; Mei Li; Jun He; Jing Chen; Peng Zhou; Zhengli Shi; Xinwen Chen; Xiaoli Xiong
• Keywords: Coronavirus; Angiotensin-converting enzyme 2

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, Africa. These all adopt tightly packed, locked, prefusion conformations. enable classification SARSr-CoV into three types, based on their receptor-binding motif (RBM) ACE2 characteristics. Type-2 often preferentially bind bat (bACE2) over hACE2. a structure type-2 BtKY72-RBD in complex with bACE2 to understand specificity. Structure-guided mutagenesis reveals that multiple synergistic mutations four regions RBM are required achieve high-affinity hACE2 binding. Similar changes can also confer another BM48-31 S-protein, which is primarily non-ACE2 results provide an understanding how may be acquired S-proteins.