morphinans and 6--guanidinonaltrindole

The κ opioid receptor (κOR) is a member of G-protein-coupled receptors, and is considered as a promising drug target for treating neurological diseases. κOR selective 6'-GNTI was proved to be a G-protein biased agonist, whereas 5'-GNTI acts as an antagonist. To investigate the molecular mechanism of how these two ligands induce different behaviors of the receptor, we built two systems containing the 5'-GNTI-κOR complex and the 6'-GNTI-κOR complex, respectively, and performed molecular dynamics simulations of the two systems. We observe that transmembrane (TM) helix 6 of the κOR rotates about 4.6(o) on average in the κOR-6'-GNTI complex. Detailed analyses of the simulation results indicate that E297(6.58) and I294(6.55) play crucial roles in the rotation of TM6. In the simulation of the κOR-5'-GNTI system, it is revealed that 5'-GNTI can stabilize TM6 in the inactive state form. In addition, the kink of TM7 is stabilized by a hydrogen bond between S324(7.47) and the residue V69(1.42) on TM1.

Topics: Allosteric Regulation; Amino Acid Motifs; Analgesics, Opioid; Cations, Monovalent; Gene Expression; Guanidines; Humans; Hydrogen Bonding; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Morphinans; Mutation; Naltrexone; Narcotic Antagonists; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Receptors, Opioid, kappa; Recombinant Proteins; Sodium

Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5'-GNTI is an antagonist while 6'-GNTI is an agonist of the kappaOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure of the ligand-receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the "3-7 lock" between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those two switches are interdependent.

Topics: Binding Sites; Guanidines; Ligands; Models, Molecular; Molecular Dynamics Simulation; Morphinans; Naltrexone; Protein Structure, Tertiary; Receptors, Opioid, kappa