Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain. / Schuurs, Zachariah P.; Hammond, Edward; Elli, Stefano; Rudd, Timothy R.; Mycroft-West, Courtney J.; Lima, Marcelo A.; Skidmore, Mark A.; Karlsson, Richard; Chen, Yen-Hsi; Bagdonaite, Ieva; Yang, Zhang; Ahmed, Yassir A.; Richard, Derek J.; Turnbull, Jeremy; Ferro, Vito; Coombe, Deirdre R.; Gandhi, Neha S.
In: Computational and Structural Biotechnology Journal, Vol. 19, 2021, p. 2806-2818.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain
AU - Schuurs, Zachariah P.
AU - Hammond, Edward
AU - Elli, Stefano
AU - Rudd, Timothy R.
AU - Mycroft-West, Courtney J.
AU - Lima, Marcelo A.
AU - Skidmore, Mark A.
AU - Karlsson, Richard
AU - Chen, Yen-Hsi
AU - Bagdonaite, Ieva
AU - Yang, Zhang
AU - Ahmed, Yassir A.
AU - Richard, Derek J.
AU - Turnbull, Jeremy
AU - Ferro, Vito
AU - Coombe, Deirdre R.
AU - Gandhi, Neha S.
PY - 2021
Y1 - 2021
N2 - 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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
AB - 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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
KW - Heparan sulfate
KW - SARS-CoV-2
KW - COVID-19
KW - Spike protein
KW - Heparin
KW - Coronavirus
KW - Cosolvent MD simulations
KW - DELPHI WEB SERVER
KW - HEPARAN-SULFATE
KW - MOLECULAR-DYNAMICS
KW - SOFTWARE NEWS
KW - VISUALIZATION
KW - ANTITHROMBIN
KW - GROMACS
KW - SYSTEM
KW - GUI
U2 - 10.1016/j.csbj.2021.05.002
DO - 10.1016/j.csbj.2021.05.002
M3 - Journal article
C2 - 33968333
VL - 19
SP - 2806
EP - 2818
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
SN - 2001-0370
ER -
ID: 291018380