Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind to platelet-derived growth factor receptor alpha (PDGFRα) and transforming growth factor beta receptor 3 (TGFβR3) to gain entry into multiple cell types. This complex is targeted by potent neutralizing antibodies and represents an important candidate for therapeutics against HCMV. Here, we determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFβR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFβR3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFRα interaction has an inhibitory effect on PDGFRα signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.

人类巨细胞病毒 (HCMV) 感染大多数人群，是导致先天性出生缺陷的主要病毒原因。HCMV 利用糖蛋白 gHgLgO（三聚体）与血小板衍生生长因子受体 α（PDGFRα）和转化生长因子 β 受体 3（TGFβR3）结合以进入多种细胞类型。这种复合物是强效中和抗体的靶点，是 HCMV 治疗的重要候选者。在这里，我们确定了三聚体的三个低温电子显微镜 (cryo-EM) 结构及其与四个结合伙伴相互作用的细节：受体蛋白 PDGFRα 和 TGFβR3 以及两种广泛中和的抗体。三聚体与 PDGFRα 和 TGFβR3 的结合是相互排斥的，表明它们作为独立的进入受体起作用。此外，三聚体-PDGFRα 相互作用对 PDGFRα 信号传导具有抑制作用。我们的结果为理解 HCMV 受体的参与、中和和针对 HCMV 的抗病毒策略的开发提供了一个框架。