Journal Article

Structure of the human kappa-opioid receptor in complex with JDTic

Cherezov, Vadim, Wacker, Daniel, Roth, Bryan L, Liu, Wei, Han, Gye Won, Mileni, Mauro, Mascarella, S Wayne, Mosier, Philip D, Vardy, Eyal, Thompson, Aaron A, Huang, Xi-Ping, Wu, Huixian, Stevens, Raymond C, Carroll, F Ivy, Katritch, Vsevolod, Westkaemper, Richard B

2012

Overview

Opioid receptorsmediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulationof pain, respiratory drive,mood, and-in the case of κ-opioid receptor (κ-OR)-dysphoria andpsychotomimesis. Here wereport the crystal structure of the human κ-ORin complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9A resolution.The structure reveals important features of the liganδ-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 59-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directedmutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR. [PUBLICATION ABSTRACT]

• Publisher: Nature Publishing Group
• Subject: Chemokines / Cholesterol / Data collection / Ligands / Peptides / Proteins