Competitive Antagonism of AMPA Receptors by Ligands of Different Classes:  Crystal Structure of ATPO Bound to the GluR2 Ligand-Binding Core, in Comparison with DNQX

Hogner, Anders; Greenwood, Jeremy R.; Liljefors, Tommy; Lunn, Marie Louise; Egebjerg, Jan; Larsen, Inger Kristin; Gouaux, Eric; Kastrup, J.S.

doi:10.1021/jm020989v

Cited by 98 publications

(133 citation statements)

References 48 publications

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“…To quantify differences in the extent of domain closure, we superimposed domain 1 of each protomer in the GluR5 UBP310 and UBP302 structures on domain 1 of monomer A from the GluR5 glutamate complex. This analysis was repeated for the previously solved AMPA receptor DNQX and ATPO antagonist complexes (Armstrong and Gouaux, 2000;Hogner et al, 2003) and for the NMDA receptor NR1 5,7-dichlorokynurenic acid (DCKA) and cycloleucine (cLeu) antagonist complexes (Furukawa and Gouaux, 2003;Inanobe et al, 2005), using the appropriate parent agonist complex as the reference structure. Domain closure was quantified by calculating the rotation angle required to superimpose domain 2 of the individual complexes on their parent agonist structures after previous superposition of domain 1.…”

Section: The Ubp Glur5 Complexes Have a Hyperextended Conformationmentioning

confidence: 99%

“…Surprisingly, despite the large difference in separation of the two domains that form the ligand binding site, there is substantial conservation of bound water molecules in the GluR5 agonist and antagonist complexes. The conformation of Glu723, a key side chain in the ligand binding site, is distinct from that found in the functionally related AMPA receptor antagonist complexes and suggests that GluR5 is trapped in the resting state rather than the partially activated structure observed for the GluR2 DNQX and 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) antagonist complexes (Armstrong and Gouaux, 2000;Hogner et al, 2003).…”

Section: Introductionmentioning

confidence: 96%

“…The protein data bank (PDB) currently contains the structures of Ͼ60 iGluR agonist complexes, but strikingly, despite the vast number of antagonists that have been synthesized and that are widely used in neuroscience research, only four antagonist structures have been solved, two for the glycine-binding NR1 subunit of NMDA receptors (Furukawa and Gouaux, 2003;Inanobe et al, 2005) and two for the AMPA receptor GluR2 subunit (Armstrong and Gouaux, 2000;Hogner et al, 2003). This imbalance reflects the greater difficulty of crystallizing antagonist-bound forms of iGluRs.…”

Section: Introductionmentioning

confidence: 99%

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Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Mayer¹,

Ghosal²,

Dolman³

et al. 2006

J. Neurosci.

107

131

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Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 Å extension of the ion channel linkers in the transition from antagonist-to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.

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Section: The Ubp Glur5 Complexes Have a Hyperextended Conformationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Mayer¹,

Ghosal²,

Dolman³

et al. 2006

J. Neurosci.

107

131

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“…The GluA2 structures and previous results from biochemical, biophysical, and crystallographic studies of isolated subunits and full-length receptors (2,(10)(11)(12)(13)(14)(15) have provided a working model for understanding how agonist binding to the four clamshell-shaped LBDs pulls the linkers that connect the LBDs to the pore-lining M3 helices away from the overall axis of the channel, and how desensitization can permit agonist-bound channels to be closed. However, if the intracellular domains play any structural role in activation and desensitization is unknown.…”

mentioning

confidence: 99%

Structural rearrangement of the intracellular domains during AMPA receptor activation

Zachariassen

Katchan

Jensen

et al. 2016

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

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α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ligand-gated ion channels that mediate the majority of fast excitatory neurotransmission in the central nervous system. Despite recent advances in structural studies of AMPARs, information about the specific conformational changes that underlie receptor function is lacking. Here, we used single and dual insertion of GFP variants at various positions in AMPAR subunits to enable measurements of conformational changes using fluorescence resonance energy transfer (FRET) in live cells. We produced dual CFP/ YFP-tagged GluA2 subunit constructs that had normal activity and displayed intrareceptor FRET. We used fluorescence lifetime imaging microscopy (FLIM) in live HEK293 cells to determine distinct steady-state FRET efficiencies in the presence of different ligands, suggesting a dynamic picture of the resting state. Patch-clamp fluorometry of the double-and single-insert constructs showed that both the intracellular C-terminal domain (CTD) and the loop region between the M1 and M2 helices move during activation and the CTD is detached from the membrane. Our time-resolved measurements revealed unexpectedly complex fluorescence changes within these intracellular domains, providing clues as to how posttranslational modifications and receptor function interact.T he α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (iGluRs) reside in postsynaptic membranes in the central nervous system (1). Like the other major iGluR subtypes, the N-methyl-Daspartate receptors (NMDARs) and kainate receptors, AMPARs are ligand-gated cation channels formed by hetero-or homotetrameric assembly of the GluA1 to GluA4 subunits into a membranespanning receptor with an integral ion channel. The energy from binding of the excitatory neurotransmitter glutamate at extracellular sites triggers AMPARs to passage through functional states that can include ion channel activation, deactivation, and desensitization. The timing and interplay between the necessarily distinct conformations of these states determine both basal transmission and short-term plasticity of the postsynapse (2-4).Structures of AMPARs captured in various functional states using X-ray crystallography and cryoelectron microscopy have recently become available (5-9). Overall, the structures confirm three distinct structural layers (Fig. 1). The amino-terminal domain (ATD) and the ligand-binding domain (LBD), both distal to the membrane, and the transmembrane ion channel are each formed from four copies of the respective domain from each subunit. However, a fourth region of the receptor extends from the intracellular side of the membrane. This part of the receptor includes intracellular loops between the transmembrane helices and the variable C-terminal domain (CTD), and remains entirely unresolved in the presently available AMPAR structures.The GluA2 structures and previous results from biochemical, biophysical, and crystallographic studies of isolated subunits and fu...

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“…[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] In the planned derivatives, we always preserved the aminoacid moiety because the X-ray structural analyses of the iGluRs bilobular ligand-binding core in complex with agonists or antagonists evidenced the crucial role played by such a group. 31 In a recent paper, 32 it was described a series of derivatives generated by the incorporation of the structural elements of both kainic acid and neodysiherbaine A (neoDH), two naturally occurring pro-convulsant agents. Surprisingly, some of them, e.g.…”

Section: Introductionmentioning

confidence: 99%

Efficient synthesis of kainic acid analogues

Tamborini¹,

Mastronardi²,

Cullia³

et al. 2013

Arkivoc

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The present paper deals with an improved synthesis of two molecular hybrids of AMPA and KA, compounds CIP-A and CIP-B, and their transformation into CIOP-A and CIOP-B, the corresponding amido derivatives. Exploiting the continuous-flow technology, a significant improvement in the synthesis of the glutamate agonists CIP-A and CIP-B was accomplished, in terms of overall yield, time, and excess of ethyl chlorooximinoacetate. Moreover, we find out the HPLC conditions suitable to separate, at a preparative level, the three intermediates formed in the 1,3-dipolar cycloaddition step.

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Competitive Antagonism of AMPA Receptors by Ligands of Different Classes: Crystal Structure of ATPO Bound to the GluR2 Ligand-Binding Core, in Comparison with DNQX

Cited by 98 publications

References 48 publications

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Structural rearrangement of the intracellular domains during AMPA receptor activation

Efficient synthesis of kainic acid analogues

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