Insight into structural properties of viral G protein-coupled receptors and their role in the viral infection: IUPHAR Review 41

G protein-coupled receptors (GPCRs) are pivotal in cellular signalling and drug targeting. Herpesviruses encode GPCRs (vGPCRs) to manipulate cellular signalling, thereby regulating various aspects of the virus life cycle, such as viral spreading and immune evasion. vGPCRs mimic host chemokine receptors, often with broader signalling and high constitutive activity. This review focuses on the recent advancements in structural knowledge about vGPCRs, with an emphasis on molecular mechanisms of action and ligand binding. The structures of US27 and US28 from human cytomegalovirus (HCMV) are compared to their closest human homologue, CX₃CR1. Contrasting US27 and US28, the homotrimeric UL78 structure (HCMV) reveals more distance to chemokine receptors. Open reading frame 74 (ORF74; Kaposi's sarcoma-associated herpesvirus) is compared to CXCRs, whereas BILF1 (Epstein–Barr virus) is discussed as a putative lipid receptor. Furthermore, the roles of vGPCRs in latency and lytic replication, reactivation, dissemination and immune evasion are reviewed, together with their potential as drug targets for virus infections and virus-related diseases.