Bu Fan, Ye Gang, Turner-Hubbard Hailey, Herbst Morgan, Liu Bin, Li Fang
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Center for Emerging Viruses, University of Minnesota, Minneapolis, MN, USA.
Commun Biol. 2025 Feb 2;8(1):156. doi: 10.1038/s42003-025-07613-y.
Sudan ebolavirus (SUDV), like Ebola ebolavirus (EBOV), poses a significant threat to global health and security due to its high lethality. However, unlike EBOV, there are no approved vaccines or treatments for SUDV, and its structural interaction with the endosomal receptor NPC1 remains unclear. This study compares the glycoproteins of SUDV and EBOV (in their proteolytically primed forms) and their binding to human NPC1 (hNPC1). The findings reveal that the SUDV glycoprotein binds significantly more strongly to hNPC1 than the EBOV glycoprotein. Using cryo-EM, we determined the structure of the SUDV glycoprotein/hNPC1 complex, identifying four key residues in the SUDV glycoprotein that differ from those in the EBOV glycoprotein and influence hNPC1 binding: Ile79, Ala141, and Pro148 enhance binding, while Gln142 reduces it. Collectively, these residue differences account for SUDV's stronger binding affinity for hNPC1. This study provides critical insights into receptor recognition across all viruses in the ebolavirus genus, including their interactions with receptors in bats, their suspected reservoir hosts. These findings advance our understanding of ebolavirus cell entry, tissue tropism, and host range.
苏丹埃博拉病毒（SUDV）与埃博拉病毒（EBOV）一样，因其高致死率对全球健康与安全构成重大威胁。然而，与EBOV不同的是，目前尚无针对SUDV的获批疫苗或治疗方法，且其与内体受体NPC1的结构相互作用仍不清楚。本研究比较了SUDV和EBOV的糖蛋白（处于蛋白水解引发形式）及其与人类NPC1（hNPC1）的结合情况。研究结果表明，SUDV糖蛋白与hNPC1的结合力明显强于EBOV糖蛋白。利用冷冻电镜，我们确定了SUDV糖蛋白/hNPC1复合物的结构，鉴定出SUDV糖蛋白中与EBOV糖蛋白不同且影响hNPC1结合的四个关键残基：异亮氨酸79、丙氨酸141和脯氨酸148增强结合，而谷氨酰胺142则降低结合。总体而言，这些残基差异解释了SUDV对hNPC1更强的结合亲和力。本研究为埃博拉病毒属所有病毒的受体识别提供了关键见解，包括它们与蝙蝠（疑似储存宿主）中受体的相互作用。这些发现增进了我们对埃博拉病毒细胞进入、组织嗜性和宿主范围的理解。
