Evidence for Multiple Binding Modes in the Initial Contact Between SARS-CoV-2 Spike S1 Protein and Cell Surface Glycans** |
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| Authors: | Dr Michela Parafioriti Dr Minghong Ni Maurice Petitou Dr Courtney J Mycroft-West Dr Timothy R Rudd Dr Neha S Gandhi Prof Vito Ferro Prof Jeremy E Turnbull Dr Marcelo A Lima Dr Mark A Skidmore Prof David G Fernig Dr Edwin A Yates Dr Antonella Bisio Dr Marco Guerrini Dr Stefano Elli |
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| Institution: | 1. Department NMR and Carbohydrates Istituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”, via Giuseppe Colombo 81, 20133 Milano, Italy;2. Structural Biology, Rosalind Franklin Institute, Harwell Campus, OX11 0QS Didcot, United Kingdom;3. Analytical and Biological Sciences Research & Development, Medicines and Healthcare products Regulatory Agency, Blanche Lane, EN6 3QG South Mimms, United Kingdom;4. School of Chemistry and Physics, Queensland University of Technology, Centre for Genomics and Personalised Health, 2 George St, Brisbane, QLD, Australia;5. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia;6. Centre for Glycoscience, Keele University, Newcastle-Under-Lyme, ST5 5BG Staffordshire, United Kingdom;7. Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, L69 7ZB Liverpool, United Kingdom |
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| Abstract: | Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1-RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1-RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral-cell membrane fusion. Combining ligand-based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1-RBD of SARS CoV-2 and HS, revealing several low-specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evidence for multiple binding modes also suggest that highly specific inhibitors will not be optimal against protein S but, rather, diverse HS-based structures, characterized by high affinity and including multi-valent compounds, may be required. |
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| Keywords: | SARS-CoV-2 protein S spike heparan sulfate NMR spectroscopy MD simulation |
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