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Determination of intermediate state structures in the opening pathway of SARS-CoV-2 spike using cryo-electron microscopy.

Published version
Peer-reviewed

Type

Article

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Authors

Brotzakis, Z Faidon 
Löhr, Thomas 
Vendruscolo, Michele  ORCID logo  https://orcid.org/0000-0002-3616-1610

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, 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 this opening pathway enables us to identify a cryptic pocket that is not exposed in the open and closed states. These results underline the opportunities offered by the determination of the structures of the transient intermediate states populated during the dynamics of proteins to allow the therapeutic targeting of otherwise invisible cryptic binding sites.

Description

Keywords

34 Chemical Sciences, Coronaviruses, Emerging Infectious Diseases, Infectious Diseases, 3 Good Health and Well Being

Journal Title

Chem Sci

Conference Name

Journal ISSN

2041-6520
2041-6539

Volume Title

12

Publisher

Royal Society of Chemistry (RSC)