美国德克萨斯大学Jason S. McLellan团队揭示了克里米亚-刚果出血热病毒糖蛋白复合物的工程化与结构。相关论文于2024年12月18日在线发表在《细胞》杂志上。
研究人员表示，克里米亚-刚果出血热病毒（CCHFV）是一种通过蜱传播的病毒，能够引发严重的疾病，病例致死率为10%–40%。尽管CCHFV糖蛋白GP38和Gc的结构为病毒进入过程及中和性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的相互作用仍然未被揭示。
研究人员通过结构引导的蛋白质工程技术，构建了一个稳定的GP38-Gn-Gc异源三聚体糖蛋白复合物（GP38-GnH-DS-Gc）。该复合物的冷冻电子显微镜（cryo-EM）结构为GP38与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在预融合构象下通过Gn上的N-连接糖基帮助限制了Gc融合环的活动。
用GP38-GnH-DS-Gc免疫小鼠后，在致命的IbAr10200挑战中提供了40%的保护率。这些数据定义了GP38-Gn-Gc原型的结构，并为结构引导的疫苗抗原开发提供了模板。
附：英文原文
Title: Engineering and structures of Crimean-Congo hemorrhagic fever virus glycoprotein complexes
Author: Elizabeth McFadden, Stephanie R. Monticelli, Albert Wang, Ajit R. Ramamohan, Thomas G. Batchelor, Ana I. Kuehne, Russell R. Bakken, Alexandra L. Tse, Kartik Chandran, Andrew S. Herbert, Jason S. McLellan
Issue&Volume: 2024-12-18
Abstract: 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-GnH-DS-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-GnH-DS-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.
DOI: 10.1016/j.cell.2024.11.008
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01325-4