Three-Dimensional Structure of the Ligand-Binding Core of GluR2 in Complex with the Agonist (<i>S</i>)<i>-</i>ATPA:  Implications for Receptor Subunit Selectivity

Lunn, Marie Louise; Hogner, Anders; Stensbøl, Tine B.; Gouaux, Eric; Egebjerg, Jan; Kastrup, J.S.

doi:10.1021/jm021020+

Cited by 51 publications

(47 citation statements)

References 28 publications

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“…These structures have varied in two main respects: the angle of closure of the binding cleft and the intersubunit contacts observed, both of which have functional implications. In GluR2 S1S2, the degree of domain closure correlates closely with ligand efficacy (6,25,26). The full agonists glutamate and AMPA close the cleft to the greatest extent (19-21°) relative to the unliganded (apo) form.…”

Section: Resultsmentioning

confidence: 99%

Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid

Nanao

Green

Stern‐Bach

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

119

142

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We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the kainate receptor subunit GluR6, in complex with the agonist domoate. The structure shows the expected overall homology with AMPA and NMDA receptor subunit structures but reveals an unexpected binding mode for the side chain of domoate, in which contact is made to the larger lobe only (lobe I). In common with the AMPA receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved. Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not. The structure incorporates native glycosylation, which has not previously been described for ionotropic glutamate receptors. The position of the sugars near the subunit interface rules out their direct involvement in subunit association but leaves open the possibility of indirect modulation. Finally, we observed several tetrameric assemblies that satisfy topological constraints with respect to connection to the receptor pore, and which are therefore candidates for the native quaternary structure.crystal structure ͉ domoate ͉ glutamate receptor I onotropic glutamate receptors (iGluRs) are major mediators of rapid excitatory neurotransmission in the mammalian CNS and in consequence are involved in a wide range of physiological and pathological neural processes (1). There are three main iGluR subfamilies: AMPA, NMDA, and kainate receptors. The functional importance of both AMPA and NMDA receptors in synaptic transmission and plasticity has long been recognized. It is only recently, however, that the physiological roles of kainate receptors have begun to be delineated. Studies using selective ligands and gene ablation in mice have shown that kainate receptors are involved in the regulation of synaptic transmission and plasticity in several brain regions (2).All iGluRs are thought to share a similar overall structure, with four homologous subunits arranged around a central cationselective pore. The subunits themselves share a common membrane topology (Fig. 1A), with three transmembrane domains (termed M1, M3, and M4) and a reentrant loop similar to the P loop found in potassium channels (termed M2). This leaves two large polypeptide domains on the extracellular (synaptic) side of the membrane: the Ϸ530-aa N terminus and the domain between M3 and M4. Studies of chimeric receptors and recombinant constructs identified the Ϸ120-aa preceding M1 (termed S1) and the Ϸ140-aa M3-M4 loop (S2) as forming the agonist-binding domain (3, 4). The S1S2 domain can be expressed as a soluble polypeptide independently of the membrane-spanning domains, making it amenable to crystallization and structure determination by x-ray diffraction. In this way, structures for the S1S2 domains for the AMPA-selective subunit GluR2 (5-7) and the NMDA subunit NR1 (8) have been determined, with both proteins sharing a bilobate structure. Although no str...

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Section: Resultsmentioning

confidence: 99%

Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid

Nanao

Green

Stern‐Bach

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

119

142

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“…Among the crystal structures for GluR2 with bound agonist ligands, ATPA has the most similar ligand dimensions and subtype selectivity as those of DH. Thus, the crystal structure of GluR2 with bound ATPA (PDB 1nnp; Lunn et al, 2003) solved at 1.9-Å resolution was selected as a template for GluR5, GluR6, and KA2 modeling. For the partial agonist models, we used the 1.6-Å resolution crystal structure of GluR2 with bound kainate (PDB 1ftk; Armstrong and Gouaux, 2000); and for the antagonist ligand binding models, we used the 2.1-Å resolution crystal structure of GluR2 with bound (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (PDB 1n0t; Hogner et al, 2003).…”

Section: Marine-derived Ligands For Glutamate Receptors 1069mentioning

confidence: 99%

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Sanders¹,

Ito²,

Settimo³

et al. 2005

J Pharmacol Exp Ther

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Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogs of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15-to 25-fold lower affinity relative to that of DH for glutamate receptor (GluR)5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for kainate (KA)2 subunits, whereas MSVIII-19 displaced [ 3 H]kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptor currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogs and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.

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“…The lipid bilayer is light gray. Gouaux, 2000) and of the glycine-sensitive N-methyl-D-aspartic acid-subtype receptor NR1 (Furukawa and Gouaux, 2003) have been produced, and structures of several agonists and antagonists in complex with these constructs have been reported in recent years (Hogner et al, 2002;Kasper et al, 2002;Hogner et al, 2003;Lunn et al, 2003). The ligands bind within a cleft formed by two domains (D1 and D2), where D1 is mainly composed of residues from segment S1 and D2 mainly of residues from S2.…”

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confidence: 99%

“…A recent study on a series of complexes of 5-substituted willardiines has demonstrated that the size of a single substituent could control the degree of domain closure and thus lead to a range of ligand-dependent conformational states. Crystal structure determinations of a number of agonist complexes have shown that the constructs' conformational states are essentially unaffected by crystal packing and consequently the crystal structures of the constructs can serve as a model system for receptor-ligand binding (Kasper et al, 2002;Lunn et al, 2003). Using single-channel recordings, these conformational states were shown to control the channel open probability of discrete subconductance states of the intact ion channel and thereby control receptor activation and also influence receptor desensitization Horning and Mayer, 2004).…”

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confidence: 99%

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

Frandsen

Pickering²,

Vestergaard³

et al. 2004

Mol Pharmacol

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Ionotropic glutamate receptors mediate most rapid excitatory synaptic transmission in the mammalian central nervous system, and their involvement in neurological diseases has stimulated widespread interest in their structure and function. Despite a large number of agonists developed so far, few display selectivity among (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA)-receptor subtypes. The present study provides X-ray structures of the glutamate receptor 2 (GluR2)-selective partial agonist (S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl) propanoic acid [(S)-CPW399] in complex with the ligand-binding core of GluR2 (GluR2-S1S2J) and with a (Y702F)GluR2-S1S2J mutant. In addition, the structure of the nonselective partial agonist kainate in complex with (Y702F)GluR2-S1S2J was determined. The results show that the selectivity of (S)-CPW399 toward full-length GluR2 relative to GluR3 is reflected in the binding data on the two soluble constructs, allowing the use of (Y702F)GluR2-S1S2J as a model system for studying GluR2/GluR3 selectivity. Structural comparisons suggest that selectivity arises from disruption of a watermediated network between ligand and receptor. A D1-D2 domain closure occurs upon agonist binding. (S)-CPW399 and kainate induce greater domain closure in the Y702F mutant, indicating that these partial agonists here act in a manner more reminiscent of full agonists. Both kainate and (S)-CPW399 exhibited higher efficacy at (Y702F)GluR2(Q) i than at wild-type GluR2(Q) i . Whereas an excellent correlation exists between domain closure and efficacy of a range of agonists at full-length GluR2 determined by electrophysiology in Xenopus laevis oocytes, a direct correlation between agonist induced domain closure of (Y702F)GluR2-S1S2J and efficacy at the GluR3 receptor is not observed. Although it clearly controls selectivity, mutation of this residue alone is insufficient to explain agonist-induced conformational rearrangements occurring in this variant.Binding of (S)-glutamate to ionotropic glutamate receptors (iGluRs) is a key step in the predominant mechanism of rapid excitatory synaptic transmission among nerve cells within the mammalian central nervous system. iGluRs are important in the development and function of the central nervous system and are implicated in learning and memory formation. Furthermore, iGluRs also seem to be associated with certain neurological and psychiatric diseases (e.g., Alzheimer-type diseases, Parkinson's disease, epilepsy, stroke, amyotrophic lateral sclerosis, and schizophrenia). Therefore, the iGluRs are considered potential drug targets (Dingledine et al., 1999;Brä uner-Osborne et al., 2000). The iGluRs have been divided into three different classes: the (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), The structures reported in this article have been deposited within the Protein Databank with accession numbers 1SYH, 1SYI, and 1XHY.Article, publication date, and citation information can be found at ...

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Three-Dimensional Structure of the Ligand-Binding Core of GluR2 in Complex with the Agonist (S)-ATPA: Implications for Receptor Subunit Selectivity

Cited by 51 publications

References 28 publications

Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid

Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid

Divergent Pharmacological Activity of Novel Marine-Derived Excitatory Amino Acids on Glutamate Receptors

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

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