West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Cell Host Microbe. 2020 Mar 11;27(3):441-453.e7. doi: 10.1016/j.chom.2019.12.012. Epub 2020 Jan 30.
Rabies virus (RABV), the etiological agent for the lethal disease of rabies, is a deadly zoonotic pathogen. The RABV glycoprotein (RABV-G) is a key factor mediating virus entry and the major target of neutralizing antibodies. Here, we report the crystal structures of RABV-G solved in the free form at ∼pH-8.0 and in the complex form with a neutralizing antibody 523-11 at ∼pH-6.5, respectively. RABV-G has three domains, and the basic-to-acidic pH change results in large domain re-orientations and concomitant domain-linker re-constructions, switching it from a bent hairpin conformation into an extended conformation. During such low-pH-induced structural transitions, residues located in the domain-linker are found to play important roles in glycoprotein-mediated membrane fusion. Finally, the antibody interacts with RABV-G mainly through its heavy chain and binds to a bipartite conformational epitope in the viral protein for neutralization. These structures provide valuable information for vaccine and drug design.
狂犬病病毒（Rabies virus，RABV）是导致狂犬病的致命病原体，属于致命的人畜共患病原体。RABV 糖蛋白（RABV-G）是介导病毒进入的关键因素，也是中和抗体的主要靶标。本研究分别解析了 RABV-G 在游离状态（pH 值约为 8.0）和与中和抗体 523-11 形成复合物状态（pH 值约为 6.5）下的晶体结构。RABV-G 具有三个结构域，酸碱值的变化导致其构象发生较大转变，同时结构域连接区也发生重新构建，从弯曲的发夹构象转变为伸展构象。在这种低 pH 值诱导的结构转变过程中，发现位于结构域连接区的残基在糖蛋白介导的膜融合中发挥重要作用。最后，抗体主要通过重链与 RABV-G 相互作用，并结合病毒蛋白上的双位部分构象表位发挥中和作用。这些结构为疫苗和药物设计提供了有价值的信息。
