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Publication Abstract from PubMed

SARS-CoV-2 has emerged as a global pathogen, sparking urgent vaccine development efforts with the trimeric spike. However, the inability of antibodies like CR3022, which binds a cryptic spike epitope with nanomolar affinity, to neutralize virus, suggests a spike-based means of neutralization escape. Here, we show the SARS-CoV-2 spike to have 10% the unfolding enthalpy of a globular protein at physiological pH, where it is recognized by antibodies like CR3022, and up to 10-times more unfolding enthalpy at endosomal pH, where it sheds such antibodies, suggesting that the spike evades potentially neutralizing antibody through a pH-dependent mechanism of conformational masking. To understand the compatibility of this mechanism with ACE2-receptor interactions, we carried out binding measurements and determined cryo-EM structures of the spike recognizing up to three ACE2 molecules at both physiological and endosomal pH. In the absence of ACE2, cryo-EM analyses indicated lower pH to reduce conformational heterogeneity. Single-receptor binding domain (RBD)-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH through lowering of RBD and refolding of a pH-dependent switch. Notably, the emerging Asp614Gly strain partially destabilizes the switch that locks RBD down, thereby enhancing functional interactions with ACE2 while reducing evasion by conformational masking.

A pH-dependent switch mediates conformational masking of SARS-CoV-2 spike.,Zhou T, Tsybovsky Y, Olia AS, Gorman J, Rapp MA, Cerutti G, Katsamba PS, Nazzari A, Schon A, Wang PD, Bimela J, Shi W, Teng IT, Zhang B, Boyington JC, Chuang GY, Sampson JM, Sastry M, Stephens T, Stuckey J, Wang S, Friesner RA, Ho DD, Mascola JR, Shapiro L, Kwong PD bioRxiv. 2020 Jul 4. doi: 10.1101/2020.07.04.187989. PMID:32637958^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.