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Synthetic GPCRs for programmable sensing and control of cell behaviour
Nicholas A Kalogriopoulos1, Reika Tei1, Yuqi Yan2
1Department of Genetics, Stanford University, Stanford, CA, USA.
Nature
|December 5, 2024
Summary
Researchers developed programmable antigen-gated G-protein-coupled engineered receptors (PAGERs) that control cellular functions in response to specific antigens. This synthetic biology tool offers modularity and broad applications in therapeutics and research.
Area of Science:
- Synthetic biology
- Molecular engineering
- Cellular engineering
Background:
- Established synthetic receptors have limitations in detecting soluble antigens and lack integrated drug control.
- Chimeric antigen receptors are restricted to immobilized antigens and have a limited output scope.
Purpose of the Study:
- To engineer novel synthetic G-protein-coupled receptors (GPCRs) for antigen-dependent control of cellular processes.
- To develop a modular platform for programmable antigen-gated G-protein-coupled engineered receptors (PAGERs).
Main Methods:
- Engineered GPCR scaffolds with a conditional auto-inhibitory domain fused to nanobody binders.
- Achieved modular antigen gating where antigen binding relieves auto-inhibition, enabling drug-induced receptor activation.
- Created PAGERs responsive to diverse soluble and cell-surface antigens.
Main Results:
- Demonstrated PAGERs driving transgene expression, real-time fluorescence, and endogenous G-protein activation.
- Showcased applications including T cell migration, macrophage differentiation, therapeutic antibody secretion, and neuronal activity control.
- Successfully generated PAGERs for over a dozen biologically relevant antigens.
Conclusions:
- PAGERs provide a versatile and programmable platform for antigen-specific cellular control.
- The modular design of PAGERs facilitates broad utility in drug discovery and translational science.
- This technology enables precise manipulation of cellular functions through synthetic receptors.
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