Tethered agonist activated ADGRF1 structure reveals molecular preference for Gαq 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 Gαq preference by cryo-EM. Our structure shows that Gαq over Gαs 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. Gαs signalling is also more sensitive to mutation of TA or binding site residues than Gαq. Our work advances the understanding of aGPCR TA activation in molecular detail, identifying structural features that potentially explain preferential signal modulation.