Ligand and G-protein selectivity in the κ-opioid receptor

Abstract The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders 1 . However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects 2 . The initiation of KOR signalling requires the G i/o -family proteins including the conventional (G i1 , G i2 , G i3 , G oA and G oB ) and nonconventional (G z and G g ) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—G i1 , G oA , G z and G g —using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing G i/o -family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.