The SARS-CoV-2 Spike harbours a lipid binding pocket which modulates stability of the prefusion trimer
Summary Large trimeric Spikes decorate SARS-CoV-2 and bind host cells via receptor binding domains (RBDs). We report a conformation in which the trimer is ‘locked’ into a compact well-ordered form. This differs from previous structures where the RBD can flip up to recognise the receptor. In the ‘locked’ form regions associated with fusion transitions are stabilised and the RBD harbours curved lipids. The acyl chains bind a hydrophobic pocket in one RBD whilst the polar headgroups attach to an adjacent RBD of the trimer. By functional analogy with enteroviral pocket factors loss of the lipid would destabilise the ‘locked’ form facilitating receptor attachment, conversion to the postfusion state and virus infection. The nature of lipids available at the site of infection might affect the antigenicity/pathogenicity of released virus. These results reveal a potentially druggable pocket and suggest that the natural prefusion state occludes neutralising RBD epitopes, achieving conformational shielding from antibodies.Highlights <jats:list list-type="bullet">SARS-CoV-2 Spike can adopt a ‘locked’ conformation with all receptor binding domains (RBDs) down, likely to represent the prefusion resting stateThis ‘locked’ conformation is compact and stable, braced by lipid bound within a potentially druggable pocketKey neutralization epitopes are shielded in the ‘locked’ formLoss of lipid may trigger a cascade of events that lead to cell entry analogous to the role of lipids in enterovirus cell entry.
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 28. März Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Carrique, Loic [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.08.13.249177 |
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| PPN (Katalog-ID): |
XBI018617506 |
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| 245 | 1 | 0 | |a The SARS-CoV-2 Spike harbours a lipid binding pocket which modulates stability of the prefusion trimer |
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| 520 | |a Summary Large trimeric Spikes decorate SARS-CoV-2 and bind host cells via receptor binding domains (RBDs). We report a conformation in which the trimer is ‘locked’ into a compact well-ordered form. This differs from previous structures where the RBD can flip up to recognise the receptor. In the ‘locked’ form regions associated with fusion transitions are stabilised and the RBD harbours curved lipids. The acyl chains bind a hydrophobic pocket in one RBD whilst the polar headgroups attach to an adjacent RBD of the trimer. By functional analogy with enteroviral pocket factors loss of the lipid would destabilise the ‘locked’ form facilitating receptor attachment, conversion to the postfusion state and virus infection. The nature of lipids available at the site of infection might affect the antigenicity/pathogenicity of released virus. These results reveal a potentially druggable pocket and suggest that the natural prefusion state occludes neutralising RBD epitopes, achieving conformational shielding from antibodies.Highlights <jats:list list-type="bullet">SARS-CoV-2 Spike can adopt a ‘locked’ conformation with all receptor binding domains (RBDs) down, likely to represent the prefusion resting stateThis ‘locked’ conformation is compact and stable, braced by lipid bound within a potentially druggable pocketKey neutralization epitopes are shielded in the ‘locked’ formLoss of lipid may trigger a cascade of events that lead to cell entry analogous to the role of lipids in enterovirus cell entry | ||
| 700 | 1 | |a Duyvesteyn, Helen ME |e verfasserin |4 aut | |
| 700 | 1 | |a Malinauskas, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yuguang |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Jingshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Daming |e verfasserin |4 aut | |
| 700 | 1 | |a Walter, Thomas S |e verfasserin |4 aut | |
| 700 | 1 | |a Radecke, Julika |e verfasserin |4 aut | |
| 700 | 1 | |a Huo, Jiandong |e verfasserin |4 aut | |
| 700 | 1 | |a Ruza, Reinis R |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Pranav NM |e verfasserin |4 aut | |
| 700 | 1 | |a Fry, Elizabeth E |e verfasserin |4 aut | |
| 700 | 1 | |a Stuart, David I |e verfasserin |4 aut | |
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