tetano
Editor, Senior Moderator
Sci Adv
. 2025 Mar 14;11(11):eadr8772.
doi: 10.1126/sciadv.adr8772. Epub 2025 Mar 14. SARS-related coronavirus S-protein structures reveal synergistic RBM interactions underpinning high-affinity human ACE2 binding
Jingjing Wang[SUP] 1 [/SUP], Yong Ma[SUP] 1 [/SUP], Zimu Li[SUP] 1 2 3 [/SUP], Hang Yuan[SUP] 1 4 [/SUP], Banghui Liu[SUP] 1 [/SUP], Zexuan Li[SUP] 1 4 [/SUP], Mengzhen Su[SUP] 1 5 [/SUP], Gul Habib[SUP] 1 [/SUP], Yutong Liu[SUP] 1 [/SUP], Lutang Fu[SUP] 6 [/SUP], Peiyi Wang[SUP] 6 [/SUP], Mei Li[SUP] 2 [/SUP], Jun He[SUP] 1 [/SUP], Jing Chen[SUP] 2 [/SUP], Peng Zhou[SUP] 2 [/SUP], Zhengli Shi[SUP] 2 [/SUP], Xinwen Chen[SUP] 2 [/SUP], Xiaoli Xiong[SUP] 1 [/SUP]
Affiliations
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.
. 2025 Mar 14;11(11):eadr8772.
doi: 10.1126/sciadv.adr8772. Epub 2025 Mar 14. SARS-related coronavirus S-protein structures reveal synergistic RBM interactions underpinning high-affinity human ACE2 binding
Jingjing Wang[SUP] 1 [/SUP], Yong Ma[SUP] 1 [/SUP], Zimu Li[SUP] 1 2 3 [/SUP], Hang Yuan[SUP] 1 4 [/SUP], Banghui Liu[SUP] 1 [/SUP], Zexuan Li[SUP] 1 4 [/SUP], Mengzhen Su[SUP] 1 5 [/SUP], Gul Habib[SUP] 1 [/SUP], Yutong Liu[SUP] 1 [/SUP], Lutang Fu[SUP] 6 [/SUP], Peiyi Wang[SUP] 6 [/SUP], Mei Li[SUP] 2 [/SUP], Jun He[SUP] 1 [/SUP], Jing Chen[SUP] 2 [/SUP], Peng Zhou[SUP] 2 [/SUP], Zhengli Shi[SUP] 2 [/SUP], Xinwen Chen[SUP] 2 [/SUP], Xiaoli Xiong[SUP] 1 [/SUP]
Affiliations
- PMID: 40085715
- PMCID: PMC11908486
- DOI: 10.1126/sciadv.adr8772
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.