Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor
Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor
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DOI：
10.1016/j.cell.2019.04.006
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发表时间：
2019-06-13
期刊：
影响因子：
64.5
通讯作者：
Fremont, Daved H.
中科院分区：
文献类型：
--
作者：
Basore, Katherine;Kim, Arthur S.;Fremont, Daved H.
mxra 8是多种致关节炎甲病毒的受体，这种病毒可导致人类衰弱性acct和慢性肌肉骨骼疾病。在此，我们提出了一个2.2埃分辨率的X射线晶体结构的Mxra 8和4至5埃分辨率的冷冻电子显微镜重建Mxra 8结合基孔肯雅（CHIKV）病毒样颗粒和感染性病毒。Mxra 8胞外域含有两个链交换的Ig样结构域，以独特的二硫键连接的头对头排列定向。Mxra 8通过楔入由一个三聚体刺突中的两个相邻CHIKV E2-E1异二聚体产生的裂缝中并接合相邻刺突来结合。用完全成熟的VLP观察到两种结合模式，其中一种Mxra 8与独特的接触结合。在具有感染性CHIKV的复合物中仅观察到高亲和力结合模式，因为病毒成熟和E3占据似乎影响受体结合位点的使用。我们的研究深入了解了Mxra 8如何结合CHIKV，并为开发甲病毒进入抑制剂创造了一条途径。
Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acct and chronic musculoskeletal disease in humans. Herein, we present a 2.2 angstrom resolution X-ray crystal structure of Mxra8 and 4 to 5 angstrom resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike. Two binding modes are observed with the fully mature VLP, with one Mxra8 binding with unique contacts. Only the high-affinity binding mode was observed in the complex with infectious CHIKV, as viral maturation and E3 occupancy appear to influence receptor binding-site usage. Our studies provide insight into how Mxra8 binds CHIKV and creates a path for developing alphavirus entry inhibitors.