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Spike-Intermediates_medRxiv.pdf (39.88 MB)

Determination of Intermediate State Structures in the Opening Pathway of SARS-CoV-2 Spike Using Cryo-Electron Microscopy

preprint
submitted on 11.11.2020, 17:30 and posted on 12.11.2020, 13:22 by Zacharias Faidon Brotzakis, Thomas Lohr, Michele Vendruscolo
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID19, a highly infectious disease that is severely affecting our society and welfare systems. In order to develop therapeutic interventions against this condition, one promising strategy is to target spike, the trimeric transmembrane glycoprotein that the virus uses to recognise and bind its host cells. Here we use a metainference cryo-electron microscopy approach to determine the opening pathway that brings spike from its inactive (closed) conformation to its active (open) one. The knowledge of the structures of the intermediate states of spike along these opening pathways enables us to identify a cryptic pocket that is not exposed in the open and closed states. We then identify compounds that bind the cryptic pocket by screening a library of repurposed drugs. These results underline the opportunities offered by the determination of the structures of the intermediate states populated during the dynamics of proteins to allow the therapeutic targeting of otherwise invisible cryptic binding sites.

History

Email Address of Submitting Author

fb516@cam.ac.uk

Institution

University of Cambridge

Country

UK

ORCID For Submitting Author

0000-0001-7024-1430

Declaration of Conflict of Interest

No conflict of interest

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