Abstract

Cholecystokinin A receptor (CCK A R) belongs to family A G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal and metabolic diseases. One distinguishing feature of CCK A R is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including G s , G i and G q . However, the basis for G-protein coupling promiscuity and ligand recognition by CCK A R remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCK A R in complex with G s , G i and G q heterotrimers, respectively. CCK A R presents a similar conformation in the three structures, whereas conformational differences in the ‘wavy hook’ of the Gα subunits and ICL3 of the receptor serve as determinants in G-protein coupling selectivity. Our findings provide a framework for understanding G-protein coupling promiscuity by CCK A R and uncover the mechanism of receptor recognition by sulfated CCK-8.