Structural Basis for AMPA Receptor Activation and Ligand Selectivity: Crystal Structures of Five Agonist Complexes with the GluR2 Ligand-binding Core

Hogner, Anders; Kastrup, J.S.; Jin, Rongsheng; Liljefors, Tommy; Mayer, Mark L.; Egebjerg, Jan; Larsen, Inger Kristin; Gouaux, Eric

doi:10.1016/s0022-2836(02)00650-2

Cited by 150 publications

(284 citation statements)

References 56 publications

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“…X-ray crystallographic studies on the isolated ligand binding domain (LBD) of the glutamate receptor subunit 2 (GluR2) AMPA receptor subunit (GluR2-S1S2) show that glutamate and other agonists bind within a deep cleft between two globular domains (1 and 2) (Armstrong et al, 1998;Armstrong and Gouaux, 2000). In agonist-bound structures, domain 2 rotates around helix I ϳ20°relative to its position in apo structures (Armstrong and Gouaux, 2000;Hogner et al, 2002;Jin et al, 2002), closing the binding cleft and trapping glutamate and other agonists in the binding pocket.…”

Section: Introductionmentioning

confidence: 99%

“…Comparison of binding core structures for different agonists demonstrated that there is also a strong positive correlation between the extent to which domain 2 moves and agonist efficacy, with full agonists all producing similar amounts of LBD closure and partial agonists resulting in less closure of the binding cleft (Armstrong et al, 1998;Armstrong and Gouaux, 2000;Hogner et al, 2002;Jin et al, 2002Jin et al, , 2003. Although there is no direct evidence that LBD closure necessarily precedes channel gating, these and other results strongly suggest that closing of the LBD is the initial large-scale conformational change that triggers the subsequent gating rearrangements that result in channel opening and desensitization (Sun et al, 2002;Robert et al, 2005;Valentine and Palmer, 2005;Armstrong et al, 2006;Mayer, 2006;Ahmed et al, 2007;Hansen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Zhang¹,

Cho²,

Lolis³

et al. 2008

J. Neurosci.

118

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At most excitatory central synapses, glutamate is released from presynaptic terminals and binds to postsynaptic AMPA receptors, initiating a series of conformational changes that result in ion channel opening. Efficient transmission at these synapses requires that glutamate binding to AMPA receptors results in rapid and near-synchronous opening of postsynaptic receptor channels. In addition, if the information encoded in the frequency of action potential discharge is to be transmitted faithfully, glutamate must dissociate from the receptor quickly, enabling the synapse to discriminate presynaptic action potentials that are spaced closely in time.The current view is that the efficacy of agonists is directly related to the extent to which ligand binding results in closure of the binding domain. For glutamate to dissociate from the receptor, however, the binding domain must open. Previously, we showed that mutations in glutamate receptor subunit 2 that should destabilize the closed conformation not only sped deactivation but also altered the relative efficacy of glutamate and quisqualate. Here we present x-ray crystallographic and single-channel data that support the conclusions that binding domain closing necessarily precedes channel opening and that the kinetics of conformational changes at the level of the binding domain importantly influence ion channel gating. Our findings suggest that the stability of the closed-cleft conformation has been tuned during evolution so that glutamate dissociates from the receptor as rapidly as possible but remains an efficacious agonist.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Zhang¹,

Cho²,

Lolis³

et al. 2008

J. Neurosci.

118

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“…This cleft closure is believed to be a rigid body motion of one lobe relative to the other. Furthermore, the degree of lobe closure has been shown to be directly proportional to the extent of activation of these receptors, suggesting cleft closure in the S1S2 protein as the mechanism of activation of the receptor (7,8).The x-ray structures of the S1S2 protein in various ligated states have provided the first structural insights into the structure-function correlations in the glutamate receptor. These insights, however, are low temperature static images that are limited by the constraints of crystal-packing forces.…”

mentioning

confidence: 99%

“…In this report, we have performed a similar investigation using the GluR2-S1S2 protein, which allows us to compare the vibrational spectroscopic data with the x-ray and NMR structures that were obtained using this protein (7,8). Additionally, the signal to noise ratio of the spectra has also been improved.…”

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confidence: 99%

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

Cheng

Jayaraman

2004

Journal of Biological Chemistry

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In the present report, using vibrational spectroscopy we have probed the ligand-protein interactions for full agonists (glutamate and ␣-amino-5-methyl-3-hydroxy-4-isoxazole propionate (AMPA)) and a partial agonist (kainate) in the isolated ligand-binding domain of the GluR2 subunit of the glutamate receptor. These studies indicate differences in the strength of the interactions of the ␣-carboxylates for the various agonists, with kainate having the strongest interactions and glutamate having the weakest. Additionally, the interactions at the ␣-amine group of the agonists have also been probed by studying the environment of the non-disulfide-bonded Cys-425, which is in close proximity to the ␣-amine group. These investigations suggest that the interactions at the ␣-amine group are stronger for full agonists such as glutamate and AMPA as evidenced by the increase in the hydrogen bond strength at Cys-425. Partial agonists such as kainate do not change the environment of Cys-425 relative to the apo form, suggesting weak interactions at the ␣-amine group of kainate. In addition to probing the ligand environment, we have also investigated the changes in the secondary structure of the protein. Results clearly indicate that full agonists such as glutamate and AMPA induce similar secondary structural changes that are different from those of the partial agonist kainate; thus, a spectroscopic signature is provided for identifying the functional consequences of a specific ligand binding to this protein.Glutamate receptors are the predominant mediators of excitatory synaptic signals in the central nervous system (1-5). These receptors form cation-specific channels on binding glutamate and later enter a desensitized state in which the channel is closed, despite the presence of an agonist. Significant insights into the mechanism of agonist-induced activation and desensitization of this receptor have been obtained from the recent x-ray structures of the isolated, extracellular ligandbinding domain (S1S2) of the ␣-amino-5-methyl-3-hydroxy-4-isoxazole propionate (AMPA) 1 subtype of the glutamate receptors (6 -9). The x-ray structures of the S1S2 protein indicate a bilobed structure with the ligand-binding site located in the cleft between the lobes. The protein exists in an open structure in the apo state and undergoes varying degrees of cleft closure on binding various agonists. This cleft closure is believed to be a rigid body motion of one lobe relative to the other. Furthermore, the degree of lobe closure has been shown to be directly proportional to the extent of activation of these receptors, suggesting cleft closure in the S1S2 protein as the mechanism of activation of the receptor (7,8).The x-ray structures of the S1S2 protein in various ligated states have provided the first structural insights into the structure-function correlations in the glutamate receptor. These insights, however, are low temperature static images that are limited by the constraints of crystal-packing forces. For a more detailed investigation of spe...

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GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

Madsen¹,

Bräuner‐Osborne²,

Greenwood³

et al. 2010

Pharmaceutical Sciences Encyclopedia

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The complex functions of the mammalian central nervous system (CNS) are primarily determined by ( S )‐glutamic acid (Glu) and 4‐aminobutyric acid (GABA), which hyperpolarizes neurons via multiple receptor subtypes. Glu can act as a neurotoxin and cause injury to neurons in neurological disorders, including reversal of Glu transporters. This article discusses functionality of GABA and glutamate receptor ligands, including their therapeutic potentials in CNS disorders.

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Structural Basis for AMPA Receptor Activation and Ligand Selectivity: Crystal Structures of Five Agonist Complexes with the GluR2 Ligand-binding Core

Cited by 150 publications

References 56 publications

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

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

GABAand Glutamate Receptor Ligands and their Therapeutic Potential inCNSDisorders

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