Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
Cell. 2019 Jun 13;177(7):1714-1724.e12. doi: 10.1016/j.cell.2019.04.008. Epub 2019 May 9.
Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), cause severe and debilitating rheumatic diseases worldwide, resulting in severe morbidity and economic costs. Recently, MXRA8 was reported as an entry receptor. Here, we present the crystal structures of the mouse MXRA8, human MXRA8 in complex with the CHIKV E protein, and the cryo-electron microscopy structure of human MXRA8 and CHIKV virus-like particle. MXRA8 has two Ig-like domains with unique structural topologies. This receptor binds in the "canyon" between two protomers of the E spike on the surface of the virion. The atomic details at the interface between the two binding entities reveal that both the two domains and the hinge region of MXRA8 are involved in interaction with CHIKV E1-E2 residues from two protomers. Notably, the stalk region of MXRA8 is critical for CHIKV virus entry. This finding provides important information regarding the development of therapeutic countermeasures against those arthritogenic alphaviruses.
关节炎相关的甲病毒，如基孔肯雅病毒（CHIKV），在全球范围内导致严重且使人虚弱的风湿性疾病，造成严重的发病率和经济成本。最近，MXRA8 被报道为一种进入受体。在这里，我们呈现了鼠 MXRA8、与人 MXRA8 与 CHIKV E 蛋白复合物的晶体结构，以及人 MXRA8 和 CHIKV 病毒样颗粒的冷冻电镜结构。MXRA8 具有两个具有独特结构拓扑的 Ig 样结构域。这种受体结合在病毒粒子表面两个 E 刺突三聚体之间的“峡谷”中。两个结合实体之间界面的原子细节表明，MXRA8 的两个结构域和铰链区都参与了与来自两个三聚体的 CHIKV E1-E2 残基的相互作用。值得注意的是，MXRA8 的柄部区域对于 CHIKV 病毒进入至关重要。这一发现为针对这些关节炎相关的甲病毒的治疗对策的开发提供了重要信息。
