TY - JOUR
T1 - The SH Protein of Mumps Virus is a Druggable Pentameric Viroporin
AU - MacAulay, Nanna
AU - Bonvin, Alexandre M.J.J.
AU - Toft-Bertelsen, Trine Lisberg
AU - Kjær, Viktoria
AU - Prestel, Andreas
AU - Qvortrup, Katrine
AU - Ulven, Trond
AU - Bentzen, Bo Hjorth
AU - Spiess, Katja
AU - Devantier, Kira
AU - Kragelund, Birthe
AU - Rosenkilde, Mette Marie
AU - Sahin, Cagla
AU - Giulini, Marco
AU - Louka, Stavroula
AU - Manandhar, Asmita
N1 - Publisher Copyright:
Copyright © 2025 The Authors, some rights reserved.
PY - 2025/6/6
Y1 - 2025/6/6
N2 - 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.
AB - 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.
UR - https://www.science.org/doi/10.1126/sciadv.ads3071
U2 - 10.1126/sciadv.ads3071
DO - 10.1126/sciadv.ads3071
M3 - Article
SN - 2375-2548
VL - 11
JO - Science advances
JF - Science advances
IS - 23
M1 - eads3071
ER -