Structural of a glutamate-receptor ligand-binding core in complex with kainate

Neali Armstrong, Yu Sun, Guo Qiang Chen, Eric Gouaux

Research output: Contribution to journalArticle

578 Citations (Scopus)

Abstract

Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid), kinase (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig. 1). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke. Development of iGluR agonists and antagonists has been hampered by a lack of high- resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond. The structure indicates mechanisms for allosteric effector action and for ligand- induced channel gating. The information provided by this structure will be essential in designing new ligands.

Original languageEnglish (US)
Pages (from-to)913-917
Number of pages5
JournalNature
Volume395
Issue number6705
DOIs
StatePublished - Oct 29 1998
Externally publishedYes

Fingerprint

Kainic Acid
Glutamate Receptors
Ionotropic Glutamate Receptors
Ligands
Isoxazoles
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Huntington Disease
Neurotoxins
Encephalitis
N-Methylaspartate
Invertebrates
Ion Channels
Synaptic Transmission
Disulfides
Nervous System
Oxidation-Reduction
Parkinson Disease
Vertebrates
Glutamic Acid
Epilepsy

ASJC Scopus subject areas

  • General

Cite this

Structural of a glutamate-receptor ligand-binding core in complex with kainate. / Armstrong, Neali; Sun, Yu; Chen, Guo Qiang; Gouaux, Eric.

In: Nature, Vol. 395, No. 6705, 29.10.1998, p. 913-917.

Research output: Contribution to journalArticle

Armstrong, Neali ; Sun, Yu ; Chen, Guo Qiang ; Gouaux, Eric. / Structural of a glutamate-receptor ligand-binding core in complex with kainate. In: Nature. 1998 ; Vol. 395, No. 6705. pp. 913-917.
@article{16d11b6188f44e98a511e3c6fb1d7c62,
title = "Structural of a glutamate-receptor ligand-binding core in complex with kainate",
abstract = "Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid), kinase (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig. 1). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke. Development of iGluR agonists and antagonists has been hampered by a lack of high- resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond. The structure indicates mechanisms for allosteric effector action and for ligand- induced channel gating. The information provided by this structure will be essential in designing new ligands.",
author = "Neali Armstrong and Yu Sun and Chen, {Guo Qiang} and Eric Gouaux",
year = "1998",
month = "10",
day = "29",
doi = "10.1038/27692",
language = "English (US)",
volume = "395",
pages = "913--917",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6705",

}

TY - JOUR

T1 - Structural of a glutamate-receptor ligand-binding core in complex with kainate

AU - Armstrong, Neali

AU - Sun, Yu

AU - Chen, Guo Qiang

AU - Gouaux, Eric

PY - 1998/10/29

Y1 - 1998/10/29

N2 - Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid), kinase (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig. 1). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke. Development of iGluR agonists and antagonists has been hampered by a lack of high- resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond. The structure indicates mechanisms for allosteric effector action and for ligand- induced channel gating. The information provided by this structure will be essential in designing new ligands.

AB - Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid), kinase (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate) (Fig. 1). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke. Development of iGluR agonists and antagonists has been hampered by a lack of high- resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond. The structure indicates mechanisms for allosteric effector action and for ligand- induced channel gating. The information provided by this structure will be essential in designing new ligands.

UR - http://www.scopus.com/inward/record.url?scp=0032578635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032578635&partnerID=8YFLogxK

U2 - 10.1038/27692

DO - 10.1038/27692

M3 - Article

VL - 395

SP - 913

EP - 917

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6705

ER -