McFadden Elizabeth, Monticelli Stephanie R, Wang Albert, Ramamohan Ajit R, Batchelor Thomas G, Kuehne Ana I, Bakken Russell R, Tse Alexandra L, Chandran Kartik, Herbert Andrew S, McLellan Jason S
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA; The Geneva Foundation, Tacoma, WA 98402, USA.
Cell. 2025 Jan 23;188(2):303-315.e13. doi: 10.1016/j.cell.2024.11.008. Epub 2024 Dec 18.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn-Gc). A cryo-electron microscopy (cryo-EM) structure of this complex provides the molecular basis for GP38's association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-Gn-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.
克里米亚-刚果出血热病毒（CCHFV）是一种蜱传病毒，可导致人类严重疾病，病死率为10%-40%。尽管CCHFV糖蛋白GP38和Gc的结构为病毒进入机制以及中和抗体和保护性抗体的表位提供了见解，但糖蛋白Gn的结构及其与GP38和Gc的相互作用仍不清楚。在此，我们利用结构导向的蛋白质工程技术制备了一种稳定的GP38-Gn-Gc异源三聚体糖蛋白复合物（GP38-Gn-Gc）。该复合物的冷冻电子显微镜（cryo-EM）结构为GP38在病毒表面的结合提供了分子基础，揭示了Gn的结构，并表明GP38-Gn通过与Gn相连的N-连接聚糖，在融合前构象中抑制Gc融合环。用GP38-Gn-Gc免疫可使小鼠对致死性IbAr10200攻击产生40%的保护作用。这些数据确定了GP38-Gn-Gc原体的结构，并为结构导向的疫苗抗原开发提供了模板。
