Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment
Abstract
The filoviruses are etiological agents of life-threatening hemorrhagic fever with high mortality rate and risk of potential outbreak. Among members of this family, the Ebola (EBOV), Sudan (SUDV), and Marburg (MARV) viruses are considered the most pathogenic for humans. The ebolavirus nucleoprotein (NP) is the most abundant protein in infected cells and is essential for viral transcription and replication; thus, it represents an attractive target for therapeutic intervention. Here, we present the structure of SUDV NP in complex with the amino-terminal portion of the phosphoprotein VP35 at 2.3 Å. This structure captures VP35 chaperoning SUDV NP in a monomeric and RNA-free state. This transient state has been proposed to be key to maintaining a pool of monomeric and RNA-free NPs prior to NP-NP polymerization and encapsidation of the viral RNA genome. This structure also reveals a newly visualized interaction between NP and VP35, a well-defined beta sheet that is not present in previous structures. Affinity binding assays demonstrate that this beta sheet is essential for maintaining the high-affinity interaction between VP35 and a hydrophobic pocket on SUDV NP, and electron microscopy indicates the importance of this binding interaction to the oligomeric state and assembly of NP in human cells. Complementarymore »
- Authors:
-
[3]
- The Scripps Research Inst., La Jolla, CA (United States); La Jolla Institute for Immunology, La Jolla, CA (United States)
- The Scripps Research Inst., La Jolla, CA (United States)
- The Scripps Research Inst., La Jolla, CA (United States); La Jolla Institute for Immunology, La Jolla, CA (United States); Skaggs Institute for Chemical Biology, La Jolla, CA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- Contributing Org.:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- OSTI Identifier:
- 1559324
- Resource Type:
- Accepted Manuscript
- Journal Name:
- mBio (Online)
- Additional Journal Information:
- Journal Name: mBio (Online); Journal Volume: 10; Journal Issue: 4; Journal ID: ISSN 2150-7511
- Publisher:
- American Society for Microbiology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Landeras-Bueno, Sara, Oda, Shun-ichiro, Norris, Michael J., Li Salie, Zhe, Guenaga, Javier, Wyatt, Richard T., and Saphire, Erica Ollmann. Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment. United States: N. p., 2019.
Web. doi:10.1128/mbio.00734-19.
Landeras-Bueno, Sara, Oda, Shun-ichiro, Norris, Michael J., Li Salie, Zhe, Guenaga, Javier, Wyatt, Richard T., & Saphire, Erica Ollmann. Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment. United States. https://doi.org/10.1128/mbio.00734-19
Landeras-Bueno, Sara, Oda, Shun-ichiro, Norris, Michael J., Li Salie, Zhe, Guenaga, Javier, Wyatt, Richard T., and Saphire, Erica Ollmann. Tue .
"Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment". United States. https://doi.org/10.1128/mbio.00734-19. https://www.osti.gov/servlets/purl/1559324.
@article{osti_1559324,
title = {Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment},
author = {Landeras-Bueno, Sara and Oda, Shun-ichiro and Norris, Michael J. and Li Salie, Zhe and Guenaga, Javier and Wyatt, Richard T. and Saphire, Erica Ollmann},
abstractNote = {The filoviruses are etiological agents of life-threatening hemorrhagic fever with high mortality rate and risk of potential outbreak. Among members of this family, the Ebola (EBOV), Sudan (SUDV), and Marburg (MARV) viruses are considered the most pathogenic for humans. The ebolavirus nucleoprotein (NP) is the most abundant protein in infected cells and is essential for viral transcription and replication; thus, it represents an attractive target for therapeutic intervention. Here, we present the structure of SUDV NP in complex with the amino-terminal portion of the phosphoprotein VP35 at 2.3 Å. This structure captures VP35 chaperoning SUDV NP in a monomeric and RNA-free state. This transient state has been proposed to be key to maintaining a pool of monomeric and RNA-free NPs prior to NP-NP polymerization and encapsidation of the viral RNA genome. This structure also reveals a newly visualized interaction between NP and VP35, a well-defined beta sheet that is not present in previous structures. Affinity binding assays demonstrate that this beta sheet is essential for maintaining the high-affinity interaction between VP35 and a hydrophobic pocket on SUDV NP, and electron microscopy indicates the importance of this binding interaction to the oligomeric state and assembly of NP in human cells. Complementary structure-directed mutagenesis identifies critical residues conserved across the filovirus family that could be targeted by broadly effective antivirals.},
doi = {10.1128/mbio.00734-19},
journal = {mBio (Online)},
number = 4,
volume = 10,
place = {United States},
year = {Tue Jul 23 00:00:00 EDT 2019},
month = {Tue Jul 23 00:00:00 EDT 2019}
}
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Works referencing / citing this record:
Reporter Assays for Ebola Virus Nucleoprotein Oligomerization, Virion-Like Particle Budding, and Minigenome Activity Reveal the Importance of Nucleoprotein Amino Acid Position 111
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Reporter Assays for Ebola Virus Nucleoprotein Oligomerization, Virion-Like Particle Budding, and Minigenome Activity Reveal the Importance of Nucleoprotein Amino Acid Position 111
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