Ionotropic Glutamate Receptors (iGluRs): Overview of iGluR2 ligand binding domain in complex with agonists and antagonists

Ionotropic glutamate receptors (iGluRs) constitute a family of ligand gated ion channels subdivided in three classes, NMDA, AMPA (iGluA1-4) and KA (1-5) according to the agonists that selectively activate them. iGluRs are tetrameric assemblies of highly homologous receptor subunits. They are critically important for normal brain function and are considered to be involved on neurological disorders and degenerative diseases such as schizophrenia, Alzheimer’s disease, brain damage following stroke and epilepsy. Since the first publication of the structure of recombinant soluble protein of ligand binding domain of GluA2 extensive studies on this group of receptors were performed and many crystal structures as complexes of GluA2-LBD with agonists, partial agonists and antagonists were obtained. The structural information in combination with functional data makes good platform for consecutive investigation and design of new selective drugs which will be used in treatment of neurodegerative diseases.

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Dynamics and allostery of the ionotropic glutamate receptors and the ligand binding domain

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.24977 ◽

2016 ◽

Vol 84 (2) ◽

pp. 267-277 ◽

Cited By ~ 1

Author(s):

Dror Tobi

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Binding Domain ◽

Ligand Binding Domain ◽

Ionotropic Glutamate Receptors

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Structurally Variable Regions of the Ligand-Binding Domain of Ionotropic Glutamate Receptors Link Dynamics and Functional Properties

Biophysical Journal ◽

10.1016/j.bpj.2009.12.2848 ◽

2010 ◽

Vol 98 (3) ◽

pp. 524a

Author(s):

Rodney E. Versace ◽

Marco Ceruso

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Functional Properties ◽

Binding Domain ◽

Ligand Binding Domain ◽

Ionotropic Glutamate Receptors ◽

Variable Regions

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How well can molecular modelling predict the crystal structure: the case of the ligand-binding domain of glutamate receptors

Trends in Pharmacological Sciences ◽

10.1016/s0165-6147(99)01443-1 ◽

2000 ◽

Vol 21 (3) ◽

pp. 87-92 ◽

Cited By ~ 22

Author(s):

Yoav Paas ◽

Anne Devillers-Thiéry ◽

Vivian I Teichberg ◽

Jean-Pierre Changeux ◽

Miriam Eisenstein

Keyword(s):

Crystal Structure ◽

Ligand Binding ◽

Glutamate Receptors ◽

Molecular Modelling ◽

Binding Domain ◽

Ligand Binding Domain

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The macro- and microarchitectures of the ligand-binding domain of glutamate receptors

Trends in Neurosciences ◽

10.1016/s0166-2236(97)01184-3 ◽

1998 ◽

Vol 21 (3) ◽

pp. 117-125 ◽

Cited By ~ 57

Author(s):

Yoav Paas

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Binding Domain ◽

Ligand Binding Domain

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Coupled Control of Desensitization and Gating by the Ligand Binding Domain of Glutamate Receptors

Neuron ◽

10.1016/j.neuron.2012.04.020 ◽

2012 ◽

Vol 74 (5) ◽

pp. 845-857 ◽

Cited By ~ 32

Author(s):

Anna L. Carbone ◽

Andrew J.R. Plested

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Binding Domain ◽

Ligand Binding Domain

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Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists†

Biochemistry ◽

10.1021/bi8013196 ◽

2008 ◽

Vol 47 (52) ◽

pp. 13831-13841 ◽

Cited By ~ 16

Author(s):

Avinash Gill ◽

Amanda Birdsey-Benson ◽

Brian L. Jones ◽

Leslie P. Henderson ◽

Dean R. Madden

Keyword(s):

Ligand Binding ◽

Crystal Structures ◽

Ampa Receptor ◽

Receptor Activation ◽

Binding Domain ◽

Ligand Binding Domain ◽

Partial Agonists ◽

Cleft Closure

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The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins

Neuron ◽

10.1016/0896-6273(93)90269-w ◽

1993 ◽

Vol 11 (1) ◽

pp. 41-52 ◽

Cited By ~ 487

Author(s):

Patrick J. O'Hara ◽

Paul O. Sheppard ◽

Henning Thógersen ◽

Domenick Venezia ◽

Betty A. Haldeman ◽

...

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Binding Proteins ◽

Binding Domain ◽

Ligand Binding Domain ◽

Metabotropic Glutamate ◽

Periplasmic Binding Proteins

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Chemistry and Conformation of the Ligand-binding Domain of GluR2 Subtype of Glutamate Receptors

Journal of Biological Chemistry ◽

10.1074/jbc.m403111200 ◽

2004 ◽

Vol 279 (25) ◽

pp. 26346-26350 ◽

Cited By ~ 15

Author(s):

Qing Cheng ◽

Vasanthi Jayaraman

Keyword(s):

Ligand Binding ◽

Glutamate Receptors ◽

Binding Domain ◽

Ligand Binding Domain

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Structure of the Glutamate-Like Receptor GLR3.2 ligand-binding domain

10.1101/2019.12.23.887497 ◽

2019 ◽

Author(s):

Shanti Pal Gangwar ◽

Marriah Green ◽

Alexander I. Sobolevsky

Keyword(s):

Ligand Binding ◽

Structural Information ◽

Sequence Similarity ◽

Evolutionary Relationship ◽

Wound Response ◽

Binding Domain ◽

Ligand Binding Domain ◽

Amino Acid Sequence Similarity ◽

Control Seed ◽

Physiological Processes

AbstractGlutamate-like receptors (GLRs) in plants play an important role in a number of physiological processes, including wound response, stomatal aperture control, seed germination, root development, innate immune responses, pollen tube growth and morphogenesis. GLRs share amino acid sequence similarity with ionotropic glutamate receptors (iGluRs) that mediate neurotransmission in the nervous system of vertebrates. In contrast to iGluRs, however, for which numerous full-length structures are available, the structural information about the plant GLRs has been missing. Here we determine crystal structures of Arabidopsis thaliana GLR3.2 ligand-binding domain (LBD) in complex with glycine and methionine to 1.57 and 1.86 Å resolution, respectively. Our structures show a fold similar to iGluRs, with several secondary structure elements either missing or different. The closed clamshell conformation of GLR3.2 LBD suggests that both glycine and methionine act as agonists. The structures reveal molecular determinants of ligand binding and explain the promiscuity of GLRs’ ligand activation compared to iGluRs. Structural similarities of LBDs confirm an evolutionary relationship between GLRs and iGluRs and predict common molecular principles of their gating mechanisms that are driven by the bilobed clamshell-like LBDs.

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