Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Hald, Helle; Naur, Peter; Pickering, Darryl S.; Sprogoe, D.; Madsen, Ulf; Timmermann, Daniel B.; Ahring, Philip K.; Liljefors, Tommy; Schousboe, Arne; Egebjerg, Jan; Gajhede, Michael; Kastrup, J.S.

doi:10.1074/jbc.m700137200

Cited by 48 publications

(30 citation statements)

References 52 publications

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“…It should be noted that the glutamate-bound forms of the GluR6 and GluR5 ligand binding domains exhibit similar distances between residue 398 and residues 666 and 689, thus allowing for such a comparison (18,33).…”

Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

“…The three antagonist-bound structures of GluR5 have slightly varying degrees of open clefts relative to the full agonist glutamate-bound state, with the cleft being 28 -30°more open in the ATPO, UBP-310, and UBP-302 antagonist-bound states (18,33). Apart from the small changes in the extent of cleft opening, the axis of rotation in the ATPO structure is also different from that in the UBP-310-and UBP-302-bound states (Fig.…”

Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

“…Because there are no apo state or antagonist-bound structures available for the GluR6 ligand binding domain, the distance change between the apo state and glutamate-bound state for GluR6 is compared with the changes between the three antagonist-bound structures and the glutamate-bound structure for the closely related ligand binding domain of the GluR5 subunit (18,33). It should be noted that the glutamate-bound forms of the GluR6 and GluR5 ligand binding domains exhibit similar distances between residue 398 and residues 666 and 689, thus allowing for such a comparison (18,33).…”

Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

“…The kainate subtype, on the other hand, is the least studied of the three ionotropic glutamate receptor subtypes. The few structures of the agonist-and antagonistbound states of the ligand binding domains of the GluR6 and GluR5 subunits of kainate receptors suggest that this subtype of receptors most likely exhibits a similar mechanism as that of the closely related AMPA subtype (13,14,17,18,33), where the extent of activation is controlled by the extent of cleft closure induced by agonist binding in the ligand binding domain. However, the structures of the agonist-bound forms of kainate receptors cover a limited range of activations; the only partial agonist structures available are those of the kainate-and domoate-bound states, which exhibit 50% of the efficacy as the full agonist glutamate (13,14,18,33).…”

mentioning

confidence: 99%

“…These three structures, however, show a range of cleft closures. Additionally, because of a shift in the orientation of domain 2, the axis of rotation between the antagonist-and glutamate-bound forms are different for the 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO)-bound state and the 2-amino-2-carboxyethyl-3-(2-carboxythiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione (UBP-310)-and (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4-dione (UBP-302)-bound states (18,33). It is therefore still unknown which of these structures most closely represents the apo state of the protein.…”

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confidence: 99%

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Luminescence Resonance Energy Transfer Investigation of Conformational Changes in the Ligand Binding Domain of a Kainate Receptor

Rambhadran

Jayaraman

2008

Journal of Biological Chemistry

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The apo state structure of the isolated ligand binding domain of the GluR6 subunit and the conformational changes induced by agonist binding to this protein have been investigated by luminescence resonance energy transfer (LRET) measurements. The LRET-based distances show that agonist binding induces cleft closure, and the extent of cleft closure is proportional to the extent of activation over a wide range of activations, thus establishing that the cleft closure conformational change is one of the mechanisms by which the agonist mediates receptor activation. The LRET distances also provide insight into the apo state structure, for which there is currently no crystal structure available. The distance change between the glutamate-bound state and the apo state is similar to that observed between the glutamate-bound and antagonist UBP-310-bound form of the GluR5 ligand binding domain, indicating that the cleft for the apo state of the GluR6 ligand binding domain should be similar to the UBP-310-bound form of GluR5. This observation implies that the apo state of GluR6 undergoes a cleft closure of 29 -30°upon binding full agonists, one of the largest observed in the glutamate receptor family.Ionotropic glutamate receptors are the main excitatory neurotransmitter receptors in the mammalian central nervous system. Glutamate binds to an extracellular domain in these receptors and mediates a series of conformational changes that ultimately result in the formation of a cation-selective channel (activation), which then subsequently closes in the continued presence of the agonist (desensitization) (1-7). The structures of the isolated ligand binding domain of the three subtypes of glutamate receptors have provided the first insight into the conformational changes and mechanism by which the agonist could control the activation and desensitization of the channel (8 -17). However, most of the structures are of the ␣-amino-5-methyl-3-hydroxy-4-isoxazole propionate (AMPA) 2 subtype, for which currently there are over 60 structures in various ligated states (8,15,18). There is also significant insight into the dynamic state of the ligand binding domain for the AMPA receptors and on the role of specific agonist-protein interactions (3, 16, 19 -32). The kainate subtype, on the other hand, is the least studied of the three ionotropic glutamate receptor subtypes. The few structures of the agonist-and antagonistbound states of the ligand binding domains of the GluR6 and GluR5 subunits of kainate receptors suggest that this subtype of receptors most likely exhibits a similar mechanism as that of the closely related AMPA subtype (13,14,17,18,33), where the extent of activation is controlled by the extent of cleft closure induced by agonist binding in the ligand binding domain. However, the structures of the agonist-bound forms of kainate receptors cover a limited range of activations; the only partial agonist structures available are those of the kainate-and domoate-bound states, which exhibit 50% of the efficacy as the full agonist glu...

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Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

Section: Conformational Changes Induced Upon Ligand Binding-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Luminescence Resonance Energy Transfer Investigation of Conformational Changes in the Ligand Binding Domain of a Kainate Receptor

Rambhadran

Jayaraman

2008

Journal of Biological Chemistry

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Structural and Pharmacological Characterization of Phenylalanine‐Based AMPA Receptor Antagonists at Kainate Receptors

Venskutonytė¹,

Frydenvang²,

Valadés³

et al. 2012

ChemMedChem

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Continued efforts into the discovery of ligands that target ionotropic glutamate receptors (iGluRs) are important for studies of the physiological roles of the various iGluR subtypes as well as for the search for drugs that can be used in the treatment of diseases of the central nervous system. A new series of phenylalanine derivatives that target iGluRs was reported to bind AMPA receptors. Herein we report our studies of these compounds at the kainate receptors GluK1-3. Several compounds bind with micromolar affinity at GluK1 and GluK3, but do not bind GluK2. The crystal structure of the most potent compound in the ligand binding domain of GluK1 revealed different modes of binding to GluK1 and GluA2, due primarily to residues Ser741 (GluK1) and Met729 (GluA2). The compound was shown to be slightly more potent at GluK1 than at AMPA receptors and to induce a domain closure similar to that observed in GluK1 structures with partial agonists.

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Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Bunch

Krogsgaard‐Larsen

2008

Medicinal Research Reviews

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(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists.

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Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5

Cited by 48 publications

References 52 publications

Luminescence Resonance Energy Transfer Investigation of Conformational Changes in the Ligand Binding Domain of a Kainate Receptor

Luminescence Resonance Energy Transfer Investigation of Conformational Changes in the Ligand Binding Domain of a Kainate Receptor

Structural and Pharmacological Characterization of Phenylalanine‐Based AMPA Receptor Antagonists at Kainate Receptors

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

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