LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)¹, a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2–E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus–receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family.

LDLRAD3 是最近定义的委内瑞拉马脑炎病毒 (VEEV) ^{1的附着和进入受体}，一种导致人类严重神经系统疾病的新世界甲病毒。在这里，我们展示了 VEEV 病毒样颗粒的近原子分辨率冷冻电子显微镜重建，以及与 LDLRAD3 胞外域的复合体。LDLRAD3 的结构域 1 是一种低密度脂蛋白受体 A 型模块，它通过楔入由两个相邻 E2-E1 异二聚体在一个三聚体尖峰中形成的裂缝中与 VEEV 结合，并接合 E2 的结构域 A 和 B 以及融合环E1。该界面的原子建模得到诱变和抗 VEEV 抗体结合竞争测定的支持。值得注意的是，VEEV 与 LDLRAD3 结合的方式类似于致关节炎的甲病毒与结构不相关的 MXRA8 受体结合的方式，但界面要小得多。