Monique van Hoek

Could one envision a synthetic receptor technology that is fully programmable, able to detect diverse extracellular antigens – both soluble and cell-attached – and convert that recognition into a wide range of intracellular responses, from transgene expression and real-time fluorescence to modulation of innate cell behavior (excitation or inhibition of neurons, induction of cell migration, etc.)? Today we report in Nature a new technology platform that provides a step in that direction: PAGERs, for Programmable Antigen-gated G protein-coupled Engineered Receptors, convert recognition of extracellular soluble or cell-attached antigens into diverse user-selected responses. PAGERs are based on G-protein coupled receptors (GPCRs), which themselves are not structurally modular, but we were able to build in modular antigen gating by fusing an antagonist peptide to the extracellular N-terminal end, and then gating the antagonist with a fused antigen-binding nanobody.  When antigen binds, it sterically interferes with the antagonist, leading to relief of receptor inhibition. Drug or agonist can then turn on PAGER. nature.com/articles/s41586-0…