Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor

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. [Image: see text]