Venezuelan equine encephalitis virus (VEEV) is an enveloped RNA virus that causes encephalitis and potentially mortality in infected humans and equines¹. At present, no vaccines or drugs are available that prevent or cure diseases caused by VEEV. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) was recently identified as a receptor for the entry of VEEV into host cells². Here we present the cryo-electron microscopy structure of the LDLRAD3 extracellular domain 1 (LDLRAD3-D1) in complex with VEEV virus-like particles at a resolution of 3.0 Å. LDLRAD3-D1 has a cork-like structure and is inserted into clefts formed between adjacent VEEV E2–E1 heterodimers in the viral-surface trimer spikes through hydrophobic and polar contacts. Mutagenesis studies of LDLRAD3-D1 identified residues that are involved in the key interactions with VEEV. Of note, some of the LDLRAD3-D1 mutants showed a significantly increased binding affinity for VEEV, suggesting that LDLRAD3-D1 may serve as a potential scaffold for the development of inhibitors of VEEV entry. Our structures provide insights into alphavirus assembly and the binding of receptors to alphaviruses, which may guide the development of therapeutic countermeasures against alphaviruses.

委内瑞拉马脑炎病毒 (VEEV) 是一种包膜 RNA 病毒，可导致受感染的人和马¹脑炎和潜在死亡。目前，尚无疫苗或药物可以预防或治愈由 VEEV 引起的疾病。低密度脂蛋白受体 A 类结构域 3 (LDLRAD3) 最近被确定为 VEEV 进入宿主细胞的受体². 在这里，我们展示了与 VEEV 病毒样颗粒复合的 LDLRAD3 细胞外结构域 1 (LDLRAD3-D1) 的低温电子显微镜结构，分辨率为 3.0 Å。LDLRAD3-D1 具有软木状结构，并通过疏水和极性接触插入病毒表面三聚体尖峰中相邻 VEEV E2-E1 异二聚体之间形成的裂缝中。LDLRAD3-D1 的诱变研究确定了参与与 VEEV 的关键相互作用的残基。值得注意的是，一些 LDLRAD3-D1 突变体对 VEEV 的结合亲和力显着增加，这表明 LDLRAD3-D1 可能作为开发 VEEV 进入抑制剂的潜在支架。我们的结构提供了对甲病毒组装和受体与甲病毒结合的见解，