Real-time conformational dynamics of SARS-CoV-2 spikes on virus particles

BioRxiv : the Preprint Server for Biology
Maolin LuWalther Mothes


SARS-CoV-2 spike (S) mediates entry into cells and is critical for vaccine development against COVID-19. S is synthesized as a precursor, processed into S1 and S2 by furin proteases, and activated for fusion when human angiotensin-converting enzyme 2 (hACE2) engages the receptor-binding domain (RBD) and when the N-terminus of S2 is proteolytically processed. Structures of soluble ectodomains and native virus particles have revealed distinct conformations of S, including a closed trimer with all RBD oriented downward, trimers with one or two RBDs up, and hACE2-stabilized conformations with up to three RBD oriented up. Real-time information that connects these structures, however, has been lacking. Here we apply single-molecule Forster Resonance Energy Transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to hACE2, S opens into the hACE2-bound S conformation through at least one on-path intermediate, with trypsin partially activating S. Conformational preferences of convalescent patient plasma and monoclonal antibodies suggest mechanisms of neutralization involving either direct competition with hACE2 f...Continue Reading

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electron microscopy

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