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The SH protein of mumps virus is a druggable pentameric viroporin
Open accessPublished version of a preprint
Abstract
Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane. Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembrane helices and oligomeric states. Here, we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild-type SH and variants in Xenopus laevis oocytes reveals the viroporin as a chloride channel, with transport facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861
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Metadata
- Authors
- Devantier, K., Toft-Bertelsen, T. L., Prestel, A., Kjær, V. M. S., Sahin, C., Giulini, M., Louka, S., Spiess, K., Manandhar, A., Qvortrup, K., Ulven, T., Bentzen, B. H., Bonvin, A. M., MacAulay, N., Kragelund, B. B., & Rosenkilde, M. M.
- Affiliations
- University of Copenhagen (DK)
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Utrecht University (NL)
- Technical University of Denmark (DK)
- Statens Serum Institut (DK)
- Corresponding author
- Kragelund, Birthe B.
- Rosenkilde, Mette M.
- ORCID
- Venue
- Science Advances
- Published
- 2025-06-06
- Volume
- 11
- Issue
- 23
- Pages
- eads3071-eads3071
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC12143350
- OpenAlex
- W4411085934
- Cited by
- 8
- References
- 2
- Citations by year
- 2026: 5 · 2025: 3
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, cc-by-nc)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- mumps virus, small hydrophobic protein, viroporins, chloride channels, antiviral drug targets, transmembrane protein structure
- MeSH terms
- Viroporin Proteins, Animals, Antiviral Agents, Humans, Models, Molecular, Mumps virus, Oocytes, Viral Proteins, Xenopus laevis, Protein Multimerization
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