Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain

Computational and Structural Biotechnology Journal

Deirdre R. Coombe¹  Jeremy Turnbull¹  Yassir A. Ahmed¹  Ieva Bagdonaite²  Marcelo A. Lima²  Richard Karlsson²  Vito Ferro³  Neha S. Gandhi³  Derek J. Richard³  Zhang Yang³  Stefano Elli⁴  Mark A. Skidmore⁵  Courtney J. Mycroft-West⁵  Yen-Hsi Chen⁵  Timothy R. Rudd⁶  Zachariah P. Schuurs⁷  Edward Hammond⁸ 

[1] Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark;Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, UK;;Copenhagen Center for Glycomics, Department of Cellular &Istituto di Ricerche Chimiche e Biochimiche “G.Ronzoni”, via Giuseppe Colombo 81, 20133 Milano, Italy;;Molecular &National Institute for Biological Standards and Control, Analytical and Biological Sciences Division, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK;QUT, Centre for Genomics and Personalised Health, Cancer and Ageing Research Program, School of Chemistry and Physics, Faculty of Science and Engineering, Institute of Health and Biomedical Innovation, 2 George Street, Brisbane, QLD 4000, Australia;Zucero Therapeutics Ltd, 1 Westlink Court, Brisbane, Queensland, Australia;

关键词: Heparan sulfate;    SARS-CoV-2;    COVID-19;    Spike protein;    Heparin;    Coronavirus;   

DOI  :  

来源: DOAJ

【 摘 要 】

SARS-CoV-2 has rapidly spread throughout the world’s population since its initial discovery in 2019. The virus infects cells via a glycosylated spike protein located on its surface. The protein primarily binds to the angiotensin-converting enzyme-2 (ACE2) receptor, using glycosaminoglycans (GAGs) as co-receptors. Here, we performed bioinformatics and molecular dynamics simulations of the spike protein to investigate the existence of additional GAG binding sites on the receptor-binding domain (RBD), separate from previously reported heparin-binding sites. A putative GAG binding site in the N-terminal domain (NTD) of the protein was identified, encompassing residues 245–246. We hypothesized that GAGs of a sufficient length might bridge the gap between this site and the PRRARS furin cleavage site, including the mutation S247R. Docking studies using GlycoTorch Vina and subsequent MD simulations of the spike trimer in the presence of dodecasaccharides of the GAGs heparin and heparan sulfate supported this possibility. The heparan sulfate chain bridged the gap, binding the furin cleavage site and S247R. In contrast, the heparin chain bound the furin cleavage site and surrounding glycosylation structures, but not S247R. These findings identify a site in the spike protein that favors heparan sulfate binding that may be particularly pertinent for a better understanding of the recent UK and South African strains. This will also assist in future targeted therapy programs that could include repurposing clinical heparan sulfate mimetics.

【 授权许可】

Unknown