Synthetic receptors, such as chimeric antigen receptors, are a powerful tool to modulate cell behavior for therapeutic purposes. However, engineering synthetic G-protein-coupled receptors (GPCRs) — the largest family of cell surface receptors — has been notoriously difficult. Writing in Nature, Kalogriopoulos et al. now create synthetic GPCRs with a modular antigen gate. These receptors can be programmed to respond to a selected antigen, triggering diverse cellular processes.

Kalogriopoulos et al. build the modular antigen gate by connecting a nanobody linked with a peptide antagonist to the N terminus of the extracellular domain of the GPCR. In the inactive state, the autoinhibitory peptide antagonist blocks receptor activation. However, when the nanobody binds to an antigen — either soluble or expressed on a cell surface — it uncouples the autoinhibitory peptide domain from the ligand binding pocket, allowing receptor activation upon ligand binding.