Chemotype-selective modes of action of κ-opioid receptor agonists.
The Journal of biological chemistry November 29, 2013 Eyal Vardy, Philip D Mosier, Kevin J Frankowski et al.
The κ-opioid receptor (KOR) is activated by diverse agonists through both shared and distinct molecular mechanisms. By docking four chemically different ligands (dynorphin A, U-69593, salvinorin A, and an octahydroisoquinolinone carboxamide) into the antagonist-bound KOR crystal structure and testing 18 mutated positions, two classes of mutations were identified: those impairing receptor function mainly by reducing ligand binding, and those impairing function without strongly affecting binding. Mutations of the latter type were located at the binding site periphery and did not interact strongly with ligands. These “functional” residues, together with water molecules seen in the crystal structure, likely help transmit the agonist binding signal to conserved rotamer switches that trigger receptor activation.