A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein

M. Gordon Joyce; Rajeshwer S. Sankhala; Wei-Hung Chen; Misook Choe; Hongjun Bai; Agnes Hajduczki; Lianying Yan; Spencer L. Sterling; Caroline E. Peterson; Ethan C. Green; Clayton Smith; Natalia de Val; Mihret Amare; Paul Scott; Eric D. Laing; Christopher C. Broder; Morgane Rolland; Nelson L. Michael; Kayvon Modjarrad

The epitope conservation within the clade explains the antigenic cross-reactivity with both human SARS-CoV and bat SARS related CoV. To date, there has been extensive structural characterization of the SARS-CoV, and MERS-CoV spike molecule and domains, which provides a framework for understanding the novel SARS-CoV-2 spike molecule (Table S2 ). In the context of the coronavirus trimeric S glycoproteins, the RBD displays two prototypical conformations either in an "up" or "down" position, with implications for receptor binding and cell entry ( Table S1 ). To further analyze these conformations, we modeled the CR3022 binding to the trimeric structures of SARS-CoV-2, SARS-CoV and MERS-CoV. The CR3022 epitope is occluded by adjacent spike protomers when the RBD is in the "down" conformation, but becomes more accessible when the spike is in a more open conformation here multiple RBD molecules are in the "up" conformation ( Figure 4) . There is still a clash of the antibody Fc1 region with the NTD from the same protomer, or an RBD from an adjacent protomer when modeled using the static structure.