Structural and energetic analyses of SARS-CoV-2 N-terminal domain characterise sugar binding pockets and suggest putative impacts of variants on COVID-19 transmission

Lam, Su Datt; Waman, Vaishali P.; Fraternali, Franca; Orengo, Christine; Lees, Jonathan G.

doi:10.1016/j.csbj.2022.11.004

Cited by 2 publications

(2 citation statements)

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“…Structural analysis of the NTD suggested four sugar-binding sites ( 72 ), including the sialoside-binding pocket previously proposed ( 39 ). Mutations in the NTD of the Omicron variant increased the predicted SA-binding energy compared to the original Wuhan-1 strain, which may contribute to the increased transmission of the Omicron lineage ( 72 ). However, nuclear magnetic resonance experiments demonstrated that spikes from the Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) strains have depleted binding to α2,3-linked sialosides as compared to that observed for the Wuhan-1 strain ( 43 ).…”

Section: Discussionmentioning

confidence: 79%

“…The relationship between S sequence variation and glycan binding requires further investigation. Structural analysis of the NTD suggested four sugar-binding sites (72), including the sialoside-binding pocket previously proposed (39). Mutations in the NTD of the Omicron variant increased the predicted SA-binding energy compared to the original Wuhan-1 strain, which may contribute to the increased transmission of the Omicron lineage (72).…”

Section: Discussionmentioning

confidence: 93%

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Single-molecule imaging reveals allosteric stimulation of SARS-CoV-2 spike receptor binding domain by host sialic acid

Díaz-Salinas,

Jain,

Durham

et al. 2024

Sci. Adv.

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Conformational dynamics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S) mediate exposure of the binding site for the cellular receptor, angiotensin-converting enzyme 2 (ACE2). The N-terminal domain (NTD) of S binds terminal sialic acid (SA) moieties on the cell surface, but the functional role of this interaction in virus entry is unknown. Here, we report that NTD-SA interaction enhances both S-mediated virus attachment and ACE2 binding. Through single-molecule Förster resonance energy transfer imaging of individual S trimers, we demonstrate that SA binding to the NTD allosterically shifts the S conformational equilibrium, favoring enhanced exposure of the ACE2-binding site. Antibodies that target the NTD block SA binding, which contributes to their mechanism of neutralization. These findings inform on mechanisms of S activation at the cell surface.

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