Tethered agonist activated ADGRF1 structure reveals molecular preference for Gα _q signalling

Adhesion G-Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to modulate cell signalling. We report here that ADGRF1 is the first class B GPCR shown to signal through all major G-protein classes and identify the structural basis for its Gα _q preference by cryo-EM. Our structure shows that Gα _q over Gα _s preference in ADGRF1 derives from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helices VII and VIII at the site of Gα recruitment. Gα _s signalling is also more sensitive to mutation of TA or binding site residues than Gα _q . Our work advances the understanding of aGPCR TA activation in molecular detail, identifying structural features that potentially explain preferential signal modulation.