Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2006 Mar 15;2611:2852-61. doi: 10.1523/JNEUROSCI.0123-06.2005.
Show Gene links
Show Anatomy links
Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists.
Mayer ML
,
Ghosal A
,
Dolman NP
,
Jane DE
.
???displayArticle.abstract???
Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 A extension of the ion channel linkers in the transition from antagonist- to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.
Arinaminpathy,
Binding site flexibility: molecular simulation of partial and full agonists within a glutamate receptor.
2006, Pubmed
Arinaminpathy,
Binding site flexibility: molecular simulation of partial and full agonists within a glutamate receptor.
2006,
Pubmed
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed
Armstrong,
Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes.
2003,
Pubmed
,
Xenbase
Bräuner-Osborne,
Ligands for glutamate receptors: design and therapeutic prospects.
2000,
Pubmed
Brünger,
Crystallography & NMR system: A new software suite for macromolecular structure determination.
1998,
Pubmed
Chen,
Functional characterization of a potassium-selective prokaryotic glutamate receptor.
1999,
Pubmed
,
Xenbase
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Dolman,
Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.
2005,
Pubmed
Esnouf,
An extensively modified version of MolScript that includes greatly enhanced coloring capabilities.
1997,
Pubmed
Foucaud,
Structural model of the N-methyl-D-aspartate receptor glycine site probed by site-directed chemical coupling.
2003,
Pubmed
,
Xenbase
Furukawa,
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core.
2003,
Pubmed
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Hogner,
Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX.
2003,
Pubmed
Honoré,
Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists.
1988,
Pubmed
Horning,
Regulation of AMPA receptor gating by ligand binding core dimers.
2004,
Pubmed
Inanobe,
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
2005,
Pubmed
,
Xenbase
Jin,
Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate.
2002,
Pubmed
,
Xenbase
Jin,
Structural basis for partial agonist action at ionotropic glutamate receptors.
2003,
Pubmed
,
Xenbase
Jin,
Mechanism of positive allosteric modulators acting on AMPA receptors.
2005,
Pubmed
Jones,
Electron-density map interpretation.
1997,
Pubmed
Mamonova,
Protein flexibility using constraints from molecular dynamics simulations.
2005,
Pubmed
Mayer,
Mechanisms for ligand binding to GluR0 ion channels: crystal structures of the glutamate and serine complexes and a closed apo state.
2001,
Pubmed
Mayer,
Structure and function of glutamate receptor ion channels.
2004,
Pubmed
Mayer,
Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.
2005,
Pubmed
Mayer,
Glutamate receptor ion channels.
2005,
Pubmed
McCoy,
Likelihood-enhanced fast translation functions.
2005,
Pubmed
McFeeters,
Structural mobility of the extracellular ligand-binding core of an ionotropic glutamate receptor. Analysis of NMR relaxation dynamics.
2002,
Pubmed
Merritt,
Raster3D: photorealistic molecular graphics.
1997,
Pubmed
More,
Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist.
2004,
Pubmed
Moretti,
Model structures of the N-methyl-D-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands.
2004,
Pubmed
Mulle,
Subunit composition of kainate receptors in hippocampal interneurons.
2000,
Pubmed
Nanao,
Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid.
2005,
Pubmed
Naur,
Crystal structure of the kainate receptor GluR5 ligand-binding core in complex with (S)-glutamate.
2005,
Pubmed
Painter,
A molecular viewer for the analysis of TLS rigid-body motion in macromolecules.
2005,
Pubmed
Pentikäinen,
Selective agonist binding of (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and 2S-(2alpha,3beta,4beta)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) receptors: a molecular modeling study.
2003,
Pubmed
Quiocho,
Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes.
1996,
Pubmed
Rosenmund,
The tetrameric structure of a glutamate receptor channel.
1998,
Pubmed
Sun,
Mechanism of glutamate receptor desensitization.
2002,
Pubmed
Terwilliger,
Automated MAD and MIR structure solution.
1999,
Pubmed
Valentine,
Microsecond-to-millisecond conformational dynamics demarcate the GluR2 glutamate receptor bound to agonists glutamate, quisqualate, and AMPA.
2005,
Pubmed
Winn,
Use of TLS parameters to model anisotropic displacements in macromolecular refinement.
2001,
Pubmed
