Devantier Kira, Toft-Bertelsen Trine L, Prestel Andreas, Kjær Viktoria M S, Sahin Cagla, Giulini Marco, Louka Stavroula, Spiess Katja, Manandhar Asmita, Qvortrup Katrine, Ulven Trond, Bentzen Bo H, Bonvin Alexandre Mjj, MacAulay Nanna, Kragelund Birthe B, Rosenkilde Mette M
Laboratory for Molecular and Translational Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Structural Biology and NMR Laboratory (SBiNLab), The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Sci Adv. 2025 Jun 6;11(23):eads3071. doi: 10.1126/sciadv.ads3071.
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 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.
病毒感染正在增加，因此需要针对病毒蛋白的药物。病毒孔蛋白是一类不断增多的由病毒编码的跨膜寡聚蛋白，可允许小分子穿过膜。尽管病毒孔蛋白结构稀少，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，我们提供证据表明腮腺炎病毒的小疏水蛋白（SH）是一种五聚体病毒孔蛋白。从大量生物物理数据来看，全长SH的HADDOCK模型显示其细胞内C末端区域形成了对五聚体稳定至关重要的延伸结构。野生型SH及其变体在卵母细胞中的异源表达表明该病毒孔蛋白是一种氯离子通道，孔道内衬的保守含羟基残基促进了运输。SH的通道功能被小分子BIT225抑制，突出了通过SH进行抗病毒靶向治疗的潜力。
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