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

Abstract

Cholecystokinin A receptor (CCK_AR) 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_AR 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_AR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCK_AR in complex with G_s, G_i and G_q heterotrimers, respectively. CCK_AR 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_AR and uncover the mechanism of receptor recognition by sulfated CCK-8.