Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains

Yuan, Yuan; Cao, Duanfang; Zhang, Yanfang; Ma, Jun; Qi, Jianxun; Wang, Qihui; Lu, Guangwen; Wu, Ying; Yan, Jinghua; Shi, Yi; Zhang, Xinzheng; Gao, George F.

Both MERS-CoV and SARS-CoV are zoonotic pathogens and are believed to have been transmitted from a natural host, possibly bats, to humans through intermediate mammalian hosts 12, 13 . The key determinant of host specificity is the envelope-located trimeric spike (S) glycoprotein, which can be further cleaved by host proteases into an N-terminal S1 subunit and a membrane-bound C-terminal S2 region 14 . The cleaved S protein remains non-convalently associated in the metastable pre-fusion conformation. After virus endocytosis by the host cell, a second cleavage is generated, which is mediated by endolysosomal proteases (S2 0 cleavage site), allowing membrane fusion activation to occur. In the S1 subunit, the receptor binding domain (RBD, also called the C terminal domain, CTD) is localized in the C-terminal region, spanning B200 amino acids, and structural studies have revealed that the RBD consists of two subdomains: the core and external subdomains [14] [15] [16] [17] . In the S2 subunit, the heptad repeat (HR) regions are also well characterized [18] [19] [20] , and as expected, the HR1 and HR2 of MERS-CoV fold into an intra-hairpin helical structure that can assemble trimerically into a six-helix bundle (a trimer of the HR1/HR2 heterodimer), demonstrating a classical type I membrane fusion process 21 . Peptide inhibitors have been designed targeting these HR regions and been proven to be effective in vitro and in vivo 18, 19, [22] [23] [24] . These studies have provided insight into the characteristics of MERS-CoV and SARS-CoV S components; however, the overall S protein structures of these two highly pathogenic CoVs remain to be investigated. This will further enhance our understanding of S protein function and subsequent design of broadly neutralizing antibodies and vaccine immunogens.