Determination of Intermediate State Structures in the Opening Pathway of SARS-CoV-2 Spike Using Cryo-Electron Microscopy
| Autor: | Michele Vendruscolo, Thomas Löhr, Z. Faidon Brotzakis |
|---|---|
| Přispěvatelé: | Vendruscolo, Michele [0000-0002-3616-1610], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
2019-20 coronavirus outbreak
Coronavirus disease 2019 (COVID-19) Cryo-electron microscopy Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike FOS: Health sciences Molecular Dynamics Therapeutic targeting Vaccine Related 03 medical and health sciences 0302 clinical medicine Biodefense Transmembrane glycoprotein Binding site Lung 030304 developmental biology 0303 health sciences 34 Chemical Sciences Chemistry Prevention COVID-19 3 Good Health and Well Being Pneumonia General Chemistry Cell biology Infectious Diseases Emerging Infectious Diseases Pneumonia & Influenza Spike (software development) CryoEM 030217 neurology & neurosurgery |
| Zdroj: | Chemical Science |
| Popis: | 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. This files report on a) the Gaussian mixture model of the voxel map EMD-21375. b) the trajectories of the EMMI production simulation {"references":["Brotzakis et. al."]} |
| Databáze: | OpenAIRE |
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