Kira Devantier, Trine L. Toft-Bertelsen, Andreas Prestel, Viktoria M. S. Kjaer, Cagla Sahin, Marco Giulini, Stavroula Louka, Katja Spiess, Asmita Manandhar, Katrine Qvortrup, Trond Ulven, Bo Hjorth Bentzen, Alexandre Bonvin, Nanna MacAulay, Birthe B. Kragelund, Mette M Rosenkilde
{"title":"The SH Protein of Mumps Virus is a Druggable Pentameric Viroporin","authors":"Kira Devantier, Trine L. Toft-Bertelsen, Andreas Prestel, Viktoria M. S. Kjaer, Cagla Sahin, Marco Giulini, Stavroula Louka, Katja Spiess, Asmita Manandhar, Katrine Qvortrup, Trond Ulven, Bo Hjorth Bentzen, Alexandre Bonvin, Nanna MacAulay, Birthe B. Kragelund, Mette M Rosenkilde","doi":"10.1101/2024.08.09.607002","DOIUrl":null,"url":null,"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, 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.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":"3 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Biophysics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.08.09.607002","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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, 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.
病毒感染呈上升趋势,需要针对病毒蛋白的药物。病毒蛋白是一类不断增加的病毒编码跨膜寡聚蛋白,可使小分子穿过膜。尽管病毒蛋白结构稀少,但最近的研究揭示了跨膜螺旋数量和寡聚状态的多样性。在这里,我们提供了证据,证明腮腺炎病毒的小疏水蛋白(SH)是一种五聚体病毒蛋白。根据大量生物物理数据,全长 SH 的 HADDOCK 模型显示,其细胞内 C 端区域形成了对稳定五聚体至关重要的扩展结构。在爪蟾卵母细胞中异源表达野生型 SH 和变体后,发现 viroporin 是一种氯离子通道,由内衬孔的保守羟基携带残基促进。小分子 BIT225 可抑制 SH 的通道功能,突出了通过 SH 进行抗病毒靶向的潜力。