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The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor.
Kaiser, Thomas M; Kell, Steven A; Kusumoto, Hirofumi; Shaulsky, Gil; Bhattacharya, Subhrajit; Epplin, Matthew P; Strong, Katie L; Miller, Eric J; Cox, Bryan D; Menaldino, David S; Liotta, Dennis C; Traynelis, Stephen F; Burger, Pieter B.
Afiliação
  • Kaiser TM; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Kell SA; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Kusumoto H; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Shaulsky G; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Bhattacharya S; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Epplin MP; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Strong KL; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Miller EJ; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Cox BD; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Menaldino DS; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Liotta DC; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.).
  • Traynelis SF; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.) pburger@emory.edu strayne@emory.edu.
  • Burger PB; Department of Chemistry, Emory University, Atlanta, Georgia (T.M.K., S.A.K., M.P.E., K.L.S., E.J.M., B.D.C., D.S.M., D.C.L., P.B.B.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (H.K., G.S., S.B., S.F.T.) pburger@emory.edu strayne@emory.edu.
Mol Pharmacol ; 93(2): 141-156, 2018 02.
Article em En | MEDLINE | ID: mdl-29242355
N-methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de N-Metil-D-Aspartato Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de N-Metil-D-Aspartato Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article