Structures of HCMV Trimer reveal the basis for receptor recognition and cell entry

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 (PDGFR alpha) and transforming growth factor beta receptor 3 (TGF beta R3) 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 PDGFR alpha and TGF beta R3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFR alpha and TGF beta R3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFR alpha interaction has an inhibitory effect on PDGFR alpha signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.

Automated summary

HCMV uses a trimer to bind to PDGFR alpha and TGF beta R3, and the binding of these two receptors is mutually exclusive, indicating that they function as independent entry receptors. Additionally, the interaction between the trimer and PDGFR alpha inhibits PDGFR alpha signaling.