title: Molecular switches of the κ opioid receptor triggered by 6'-GNTI and 5'-GNTI.
abstract: 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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
authors.forename: Xianqiang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000701:Analgesics, Opioid / Q000737:chemistry*; D002414:Cations, Monovalent; D015870:Gene Expression; D006146:Guanidines / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009019:Morphinans / Q000737:chemistry*; D009154:Mutation; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry; D009292:Narcotic Antagonists / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012964:Sodium / Q000737:chemistry*
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; C503316:6'-guanidinonaltrindole; D000701:Analgesics, Opioid; D002414:Cations, Monovalent; D006146:Guanidines; D008024:Ligands; D009019:Morphinans; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; D009271:Naltrexone; D012964:Sodium