Structure of the μ Opioid Receptor-G(i) Protein Complex

The μ opioid receptor (μOR) is a G protein-coupled receptor (GPCR) that is the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signaling through the adenylyl cyclase-inhibiting heterotrimeric G protein G(i). We present the 3.5-Å resolution cryo-electron microscopy (cryo-EM) structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free G(i). DAMGO occupies the morphinan ligand pocket, with its N-terminus interacting with conserved receptor residues while its C-terminus engages regions important for opioid ligand selectivity. Comparison of the μOR-G(i) complex to previously determined structures of other GPCRs bound to the stimulatory G protein G(s) reveals differences in the movement of transmembrane receptor helix 6 and in the interactions between the G protein α subunit and the receptor core. Together, these results shed light into the structural features that contribute to the G(i) protein coupling specificity of the μOR.