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

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.

Automated summary

Research using cryo-electron microscopy has identified the process of SARS-CoV-2 spike transitioning from closed to open state, revealing a cryptic pocket that could be targeted for therapeutic interventions. This study emphasizes the importance of understanding transient intermediate states of proteins for developing effective treatments against invisible binding sites.