Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species

• Published in: Cell 2021-06, Vol.184 (13), p.3438-3451.e10
• Main Authors: Liu, Kefang, Pan, Xiaoqian, Li, Linjie, Yu, Feng, Zheng, Anqi, Du, Pei, Han, Pengcheng, Meng, Yumin, Zhang, Yanfang, Wu, Lili, Chen, Qian, Song, Chunli, Jia, Yunfei, Niu, Sheng, Lu, Dan, Qiao, Chengpeng, Chen, Zhihai, Ma, Dongli, Ma, Xiaopeng, Tan, Shuguang, Zhao, Xin, Qi, Jianxun, Gao, George F., Wang, Qihui
• Format: Article
• Language: English
• Subjects: ACE2; Amino Acid Sequence; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies, Monoclonal - immunology; Binding Sites - physiology; Chiroptera - immunology; Chiroptera - metabolism; Chiroptera - virology; COVID-19; COVID-19 - immunology; COVID-19 - metabolism; Host Specificity - immunology; Humans; intermediate horseshoe bat; Phylogeny; Protein Binding - physiology; RaTG13; RBD; Receptors, Virus - metabolism; SARS-CoV-2; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; Sequence Alignment
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.05.031

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs. [Display omitted] •The complex structure of RaTG13 RBD with hACE2 was determined•Binding of RaTG13 RBD to 24 additional ACE2 orthologs was evaluated•Residue 501 plays a key role in determining the potential host range of RaTG13•SARS-CoV-2 induces strong cross-protective antibodies to RaTG13 RBD Structural and molecular analysis of the receptor binding domain of RaTG13, a coronavirus phylogenetically closely related to SARS-CoV-2, bound to the human receptor ACE2 as well as ACE2 orthologs in 24 other species provides a framework to understand its host range as well as the basis of antibody cross-reactivity between the two viruses.