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Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Structures of Marburgvirus glycoprotein and its complex with NPC1 receptor
Gang Ye1,2, Fan Bu3,4, Hailey Turner-Hubbard3,4
1Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA. yeg@umn.edu.
Abstract:
Marburgviruses (MBVs) cause severe haemorrhagic fever with higher fatality rates than Ebola virus (EBOV)1-4. Here we show that the MBV glycoprotein (GP) mediates viral entry more efficiently than EBOV GP. Using cryo-EM, we determined structures of MBV GP in three states: (1) unbound; (2) bound to its endosomal receptor NPC1; and (3) complexed with a neutralizing nanobody. The glycan cap shields the receptor-binding site from NPC1 but only partially from the nanobody, enabling limited immune evasion. After glycan cap cleavage, NPC1 binds to MBV GP in a distinct orientation compared with EBOV GP, providing an additional anchor and enhancing receptor affinity. NPC1 engagement also induces substantial conformational changes in MBV GP, probably facilitating membrane fusion. Furthermore, MBV GP is susceptible to the neutralizing nanobody, which mimics NPC1 at the receptor-binding site. Together, our findings reveal MBV GP as a highly efficient entry mediator and suggest structural mechanisms that may contribute to its enhanced entry efficiency.
Insights
Marburgvirus glycoprotein (GP) mediates viral entry more efficiently than Ebola virus GP. Structural studies reveal how Marburgvirus GP
Area of Science:
- Structural Biology
- Virology
- Molecular Biology
Background:
- Marburgviruses (MBVs) cause severe hemorrhagic fever with high fatality rates.
- The viral glycoprotein (GP) mediates entry into host cells.
Purpose of the Study:
- To elucidate the structural mechanisms underlying the efficient viral entry mediated by Marburgvirus GP.
- To compare the entry mechanism of MBV GP with that of Ebola virus GP (EBOV GP).
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of MBV GP.
- Structures were resolved in unbound, receptor-bound (NPC1), and nanobody-complexed states.
Main Results:
- MBV GP exhibits higher entry efficiency than EBOV GP.
- The glycan cap partially shields the receptor-binding site, allowing limited immune evasion.
- NPC1 binds MBV GP in a distinct orientation, enhancing receptor affinity and facilitating membrane fusion.
- A neutralizing nanobody targeting the receptor-binding site demonstrates potential therapeutic strategies.
Conclusions:
- Marburgvirus GP is a highly efficient mediator of viral entry.
- Structural insights reveal mechanisms contributing to MBV's enhanced entry efficiency.
- The findings provide a basis for developing targeted antiviral interventions.
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