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PDBsum entry 4dld
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Membrane protein
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PDB id
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4dld
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References listed in PDB file
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Key reference
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Title
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Structural and pharmacological characterization of phenylalanine-Based ampa receptor antagonists at kainate receptors.
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Authors
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R.Venskutonytė,
K.Frydenvang,
E.A.Valadés,
E.Szymańska,
T.N.Johansen,
J.S.Kastrup,
D.S.Pickering.
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Ref.
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Chemmedchem, 2012,
7,
1793-1798.
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PubMed id
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Abstract
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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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Secondary reference #1
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Title
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Crystal structure of the kainate receptor glur5 ligand-Binding core in complex with (s)-Glutamate.
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Authors
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P.Naur,
B.Vestergaard,
L.K.Skov,
J.Egebjerg,
M.Gajhede,
J.S.Kastrup.
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Ref.
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FEBS Lett, 2005,
579,
1154-1160.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Ligand-binding cores of the three classes of
iGluRs. Cartoon representations of the overall structures of the
AMPA receptor GluR2-S1S2J (MolB, pdb code 1FTJ; left figure),
the kainate receptor GluR5-S1S2 (MolB; middle figure) and the
NMDA receptor NR1-S1S2 (MolA, pdb code 1PB7; right figure).
Domain D1 (primarily composed of S1 residues) is colored cyan
and D2 (primarily composed of S2 residues) is colored brown.
GluR2-S1S2J and GluR5-S1S2 were crystallized in the presence of
(S)-glutamate, whereas NR1 was crystallized in complex with
(S)-glycine. The ligands are shown in ball-and-stick
representation.
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Figure 2.
Fig. 2. Comparison of the structures of GluR5-S1S2 and
GluR2-S1S2J. (A) Structural alignment of GluR5-S1S2 and
GluR2-S1S2J. Boxes correspond to structurally conserved regions.
The Gly-Thr linker is shaded grey. (B) Superimposition of the D1
Cα-atoms of the structures of GluR5-S1S2 and GluR2-S1S2J. A
Cα-trace of the two structures is shown in stereo, with
GluR5-S1S2 coloured in green and GluR2-S1S2J in magenta. Every
10th residue of the GluR5-S1S2 structure is labeled.
(S)-glutamate is shown in ball-and-stick.
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The above figures are
reproduced from the cited reference
with permission from the Federation of European Biochemical Societies
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