Structure of the human kappa opioid receptor in complex with JDTic

Opioid receptors (ORs) mediate the actions of endogenous and exogenous opioids for many essential physiological processes including regulation of pain, respiratory drive, mood, and, in the case of κ-opioid receptors (KOR), dysphoria and psychotomimesis. Here we report the crystal structure of the human KOR (hKOR) in complex with the selective antagonist JDTic, arranged in parallel-dimers, at 2.9 angstrom resolution. The structure reveals important features of the ligand binding pocket that contribute to JDTic’s high affinity and subtype-selectivity for hKOR. Modeling of other important KOR-selective ligands, including the morphinan-derived antagonists nor-BNI and GNTI, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for hKOR subtype-selectivity along with insight essential for the design of hKOR compounds with new pharmacological properties.