A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV

Meng Yuan; Nicholas C. Wu; Xueyong Zhu; Chang-Chun D. Lee; Ray T. Y. So; Huibin Lv; Chris K. P. Mok; Ian A. Wilson

Recently, the cryo-EM structure of homotrimeric SARS-CoV-2 S protein was determined 104 (17, 18) and demonstrated that the RBD, as in other coronaviruses (19, 20) adopts two 105 different dispositions in the trimer. The RBD can then undergo a hinge-like movement to 106 transition between "up" or "down" conformations ( Fig. 3A ). ACE2 host receptor can only 107 interact with the RBD when it is in the "up" conformation, whereas the "down" 108 conformation is inaccessible to ACE2. Interestingly, the epitope of CR3022 is also only 109 accessible when the RBD is in the "up" conformation ( Fig. 3, B and C) . Furthermore, the 110 ability for CR3022 to access the RBD also depends on the relative disposition of the The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.13.991570 doi: bioRxiv preprint 6 protomer if the latter adopts a "down" conformation ( Fig. 3D) . As a homotrimer, the S 115 protein could potentially adopt four possible RBD configurations, namely none-"up", 116 single-"up", double-"up", and triple-"up". It appears that CR3022 can only bind to the S 117 protein when it is in double-"up" or triple-"up" configuration. Specifically, one molecule of 118 CR3022 can be accommodated in the double-"up" configuration ( Fig. 3E) , whereas three 119 molecules of CR3022 could potentially be accommodated in the triple-"up" configuration 120 (Fig. 3F ). Previous cryo-EM studies have also shown that the recombinant SARS-CoV S 121 protein is mostly found in the none-"up", single-"up", or double-"up" conformations (19, 122 21), but rarely in the triple-"up" conformation, even with ACE2 receptor bound (21, 22) .