Glutamate receptors at atomic resolution.

Building 35, Room 3B1002, Porter Neuroscience Research Center, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 42.35). 04/2006; 440(7083):456-62. DOI: 10.1038/nature04709
Source: PubMed

ABSTRACT At synapses throughout the brain and spinal cord, the amino-acid glutamate is the major excitatory neurotransmitter. During evolution, a family of glutamate-receptor ion channels seems to have been assembled from a kit consisting of discrete ligand-binding, ion-channel, modulatory and cytoplasmic domains. Crystallographic studies that exploit this unique architecture have greatly aided structural analysis of the ligand-binding core, but the results also pose a formidable challenge, namely that of resolving the allosteric mechanisms by which individual domains communicate and function in an intact receptor.

Download full-text


Available from: Mark L Mayer, Jul 08, 2015
1 Follower
  • Source
    • "Early evidence favored a pentameric structure for iGluRs based on the sizes of chemically cross-linked proteins and the number of distinct channel activities produced by the mixture of two subunits (Dingledine et al., 1999). However, an overwhelming number of studies analyzing structures, desensitization properties and cross-linking between subunits through cysteines now suggest that mammalian iGluRs assemble as tetramers (reviewed in Mayer, 2006; Traynelis et al., 2010). In mammals, functional ligand-gated channels can be formed from either homo-or heteromers of four subunits within the same agonist class (Rosenmund et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The plant glutamate-like receptor homologs (GLRs) are homologs of mammalian ionotropic glutamate receptors (iGluRs) which were discovered more than 10 years ago, and are hypothesized to be potential amino acid sensors in plants. Although initial progress on this gene family has been hampered by gene redundancy and technical issues such as gene toxicity; genetic, pharmacological, and electrophysiological approaches are starting to uncover the functions of this protein family. In parallel, there has been tremendous progress in elucidating the structure of animal glutamate receptors (iGluRs), which in turn will help understanding of the molecular mechanisms of plant GLR functions. In this review, we will summarize recent progress on the plant GLRs. Emerging evidence implicates plant GLRs in various biological processes in and beyond N sensing, and implies that there is some overlap in the signaling mechanisms of amino acids between plants and animals. Phylogenetic analysis using iGluRs from metazoans, plants, and bacteria showed that the plant GLRs are no more closely related to metazoan iGluRs as they are to bacterial iGluRs, indicating the separation of plant, other eukaryotic, and bacterial GLRs might have happened as early on as the last universal common ancestor. Structural similarities and differences with animal iGluRs, and the implication thereof, are also discussed.
    Frontiers in Plant Science 10/2012; 3:235. DOI:10.3389/fpls.2012.00235 · 3.64 Impact Factor
  • Source
    • "The availability of a full length iGluR structure, combined with high resolution structures for the isolated ATD and LBDs for multiple iGluR subtypes, has given unprecedented insight into the molecular function of this important family of neurotransmitter receptors. More than one hundred high resolution structures for ligand binding domain complexes for multiple iGluR subtypes with agonists, partial agonists, competitive antagonists, and allosteric modulators of desensitization, reveal with unrivalled clarity the mechanisms underlying the subtype selective pharmacology which formed the historical basis for classification of iGluR subtypes (Mayer, 2006; Pohlsgaard et al., 2011; Stawski et al., 2010; Traynelis et al., 2010). Work is rapidly progressing on the amino terminal domains, but here key questions remained to be addressed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Excitatory synaptic transmission in the brain is mediated by ligand-gated ion channels (iGluRs) activated by glutamate. Distinct from other neurotransmitter receptors, the extracellular domains of iGluRs are loosely packed assemblies with two clearly distinct layers, each of which has both local and global 2-fold axes of symmetry. By contrast, the iGluR transmembrane segments have 4-fold symmetry and share a conserved pore loop architecture found in tetrameric voltage-gated ion channels. The striking layered architecture of iGluRs revealed by the 3.6 Å resolution structure of an AMPA receptor homotetramer likely arose from gene fusion events that occurred early in evolution. Although this modular design has greatly facilitated biophysical and structural studies on individual iGluR domains, and suggested conserved mechanisms for iGluR gating, recent work is beginning to reveal unanticipated diversity in the structure, allosteric regulation, and assembly of iGluR subtypes.
    Structure 10/2011; 19(10):1370-80. DOI:10.1016/j.str.2011.08.009 · 6.79 Impact Factor
  • Source
    • "The electron microscopic picture of nicotinic acetylcholine receptors was the first to reveal the threedimensional structure of pLGIC receptors with intermediate resolution (Unwin, 1995). By now we have learned several highresolution structures of these LGIC receptor families via X-ray crystallography (Hilf and Dutzler, 2009; Mayer, 2006). All three families have pseudo-symmetric oligomeric structures (Browne et al., 2010; Changeux and Edelstein, 2005; Sobolevsky et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review focuses on basic models of allostery, the ambiguous application of the allosteric term in pharmacology illustrated by receptors, the role of thermodynamics in allosteric mechanisms, evolution and design of allostery. The initial step of ligand activation is closure of the agonist-binding cavity. Large entropy increases accompany the agonist-elicited conformational changes of pentameric ligand-gated ion channels due to cavity closure and rearrangement of transmembrane helices. The effects of point mutations on thermodynamic parameters of binding and function can reveal energetic coupling of neighbouring (and distant) amino acid residues in activation. High-order double-mutant cycle analysis and rate-equilibrium linear free-energy relationships can identify the trajectory and conformational spread of activation. Protein assembly and allostery can be deduced from colocalization and physicochemical principles. Molecular evolution has led from homooligomerization of protomers to heterotropic cooperativity and to allosteric regulation. Examples are discussed such as similar paths of protein (dis)assembly and evolution, irreversible evolution, statistical analysis of sequence homology revealing coevolution, different impacts of adaptation and evolution on hemoglobin, and the flagellar motor switch of bacteria. The driving force of dynamic allostery is associated with funnel-like free energy landscapes of protein binding and shifts in conformational fluctuations upon binding. Allostery can be designed based on our increasing knowledge of natural allosteric mechanisms and evolution. The allosteric principle has been applied for various bio/macro/molecular and signal transduction systems as well as in cognitive sciences.
    Progress in Biophysics and Molecular Biology 09/2011; 106(3):463-73. DOI:10.1016/j.pbiomolbio.2011.01.001 · 3.38 Impact Factor