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PDBsum entry 1vso
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Membrane protein
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PDB id
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1vso
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References listed in PDB file
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Key reference
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Title
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Partial agonism and antagonism of the ionotropic glutamate receptor iglur5: structures of the ligand-Binding core in complex with domoic acid and 2-Amino-3-[5-Tert-Butyl-3-(Phosphonomethoxy)-4-Isoxazolyl]propionic acid.
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Authors
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H.Hald,
P.Naur,
D.S.Pickering,
D.Sprogøe,
U.Madsen,
D.B.Timmermann,
P.K.Ahring,
T.Liljefors,
A.Schousboe,
J.Egebjerg,
M.Gajhede,
J.S.Kastrup.
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Ref.
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J Biol Chem, 2007,
282,
25726-25736.
[DOI no: ]
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PubMed id
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Abstract
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More than 50 structures have been reported on the ligand-binding core of the
ionotropic glutamate receptor iGluR2 that belongs to the
2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid-type of receptors. In
contrast, the ligand-binding core of the kainic acid-type receptor iGluR5 has
only been crystallized with three different ligands. Hence, additional
structures of iGluR5 are needed to broaden the understanding of the
ligand-binding properties of iGluR5, and the conformational changes leading to
channel opening and closing. Here, we present two structures of the
ligand-binding core of iGluR5; one as a complex with the partial agonist
(2S,3S,4S)-3-carboxymethyl-4-[(1Z,3E,5R)-5-carboxy-1-methyl-hexa-1,3-dienyl]-pyrrolidine-2-carboxylic
acid (domoic acid) and one as a complex with the antagonist
(S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid
((S)-ATPO). In agreement with the partial agonist activity of domoic acid, the
ligand-binding core of the iGluR5 complex is stabilized by domoic acid in a
conformation that is 11 degrees more open than the conformation observed in the
full agonist (S)-glutamic acid complex. This is primarily caused by the
5-carboxy-1-methyl-hexa-1,3-dienyl moiety of domoic acid and residues
Val(685)-Thr(690) of iGluR5. An even larger domain opening of 28 degrees is
introduced upon binding of the antagonist (S)-ATPO. It appears that the span of
domain opening is much larger in the ligand-binding core of iGluR5 (30 degrees )
compared with what has been observed in iGluR2 (19 degrees ). Similarly, much
larger variation in the distances between transmembrane linker residues in the
two protomers comprising the dimer is observed in iGluR5 as compared with iGluR2.
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Figure 1.
FIGURE 1. Chemical structures of domoic acid, kainic acid,
(S)-ATPO, UBP302, and UBP310. The atom numbering of domoic acid
is shown in italics and is according to Nanao et al. (46) (PDB
entry code 1YAE). The numbering of (S)-ATPO is according to
Hogner et al. (14) (PDB entry code 1N0T). See abbreviations for
compound names.
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Figure 4.
FIGURE 4. Two-dimensional ligand-receptor interaction plots
of iGluR5-S1S2 in complex with domoic acid (A) and (S)-ATPO (B).
iGluR5-S1S2 polar residues are shown as purple circles, acidic
residues as purple/red, basic residues as purple/blue, and
hydrophobic residues in green. Contacts from ligand to receptor
side chains as calculated by the program MOE are shown as green
arrows and from ligand to receptor backbone as blue arrows.
Water molecules in contact with ligands are shown as white
circles and their contacts as yellow lines. The extent of ligand
and receptor exposure is shown as blue spheres differing in size.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
25726-25736)
copyright 2007.
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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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Secondary reference #2
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Title
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Crystal structures of the kainate receptor glur5 ligand binding core dimer with novel glur5-Selective antagonists.
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Authors
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M.L.Mayer,
A.Ghosal,
N.P.Dolman,
D.E.Jane.
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Ref.
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J Neurosci, 2006,
26,
2852-2861.
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PubMed id
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Secondary reference #3
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Title
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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.
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Authors
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A.Hogner,
J.R.Greenwood,
T.Liljefors,
M.L.Lunn,
J.Egebjerg,
I.K.Larsen,
E.Gouaux,
J.S.Kastrup.
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Ref.
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J Med Chem, 2003,
46,
214-221.
[DOI no: ]
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PubMed id
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