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PDBsum entry 1n0t
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Membrane protein
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PDB id
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1n0t
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Contents |
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* Residue conservation analysis
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PDB id:
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Membrane protein
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Title:
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X-ray structure of the glur2 ligand-binding core (s1s2j) in complex with the antagonist (s)-atpo at 2.1 a resolution.
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Structure:
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Glutamate receptor 2. Chain: a, b, c, d. Fragment: glur2-flop ligand-binding core (s1s2j).. Synonym: glur-2, glur-b, glutamate receptor ionotropic, ampa 2. Engineered: yes
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Source:
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Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: rat. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Biol. unit:
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Dimer (from
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Resolution:
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2.10Å
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R-factor:
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0.194
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R-free:
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0.245
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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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Key ref:
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A.Hogner
et al.
(2003).
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.
J Med Chem,
46,
214-221.
PubMed id:
DOI:
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Date:
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15-Oct-02
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Release date:
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04-Mar-03
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PROCHECK
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Headers
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References
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P19491
(GRIA2_RAT) -
Glutamate receptor 2 from Rattus norvegicus
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Seq:
Struc:
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883 a.a.
257 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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DOI no:
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J Med Chem
46:214-221
(2003)
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PubMed id:
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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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A.Hogner,
J.R.Greenwood,
T.Liljefors,
M.L.Lunn,
J.Egebjerg,
I.K.Larsen,
E.Gouaux,
J.S.Kastrup.
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ABSTRACT
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Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion
channels that are essential for mediating fast synaptic transmission in the
central nervous system. This study presents a high-resolution X-ray structure of
the competitive antagonist
(S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid
(ATPO) in complex with the ligand-binding core of the receptor. Comparison with
the only previous structure of the ligand-binding core in complex with an
antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E.
Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of
the ligand-binding core by different sets of interactions. Computational
techniques are used to quantify the differences between these two ligands and to
map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer,
and other scaffolds could potentially be used. Whereas agonists induce
substantial domain closures compared to the apo structure, ATPO only induces
minor conformational changes. These results are consistent with the hypothesis
that domain closure is related to receptor activation. To facilitate the design
of novel AMPA receptor antagonists, we present a modified model of the binding
site that includes key residues involved in ligand recognition.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Y.Lau,
and
B.Roux
(2011).
The hidden energetics of ligand binding and activation in a glutamate receptor.
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Nat Struct Mol Biol,
18,
283-287.
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G.M.Alushin,
D.Jane,
and
M.L.Mayer
(2011).
Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists.
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Neuropharmacology,
60,
126-134.
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PDB codes:
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J.Pøhlsgaard,
K.Frydenvang,
U.Madsen,
and
J.S.Kastrup
(2011).
Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators.
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Neuropharmacology,
60,
135-150.
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R.Edwards,
J.Madine,
L.Fielding,
and
D.A.Middleton
(2010).
Measurement of multiple torsional angles from one-dimensional solid-state NMR spectra: application to the conformational analysis of a ligand in its biological receptor site.
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Phys Chem Chem Phys,
12,
13999-14008.
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A.H.Ahmed,
M.D.Thompson,
M.K.Fenwick,
B.Romero,
A.P.Loh,
D.E.Jane,
H.Sondermann,
and
R.E.Oswald
(2009).
Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain.
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Biochemistry,
48,
3894-3903.
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PDB codes:
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D.B.Tikhonov,
and
L.G.Magazanik
(2009).
Origin and molecular evolution of ionotropic glutamate receptors.
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Neurosci Behav Physiol,
39,
763-773.
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M.J.Cuneo,
L.S.Beese,
and
H.W.Hellinga
(2008).
Ligand-induced conformational changes in a thermophilic ribose-binding protein.
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BMC Struct Biol,
8,
50.
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PDB codes:
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B.H.Kaae,
K.Harpsøe,
J.S.Kastrup,
A.C.Sanz,
D.S.Pickering,
B.Metzler,
R.P.Clausen,
M.Gajhede,
P.Sauerberg,
T.Liljefors,
and
U.Madsen
(2007).
Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites.
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Chem Biol,
14,
1294-1303.
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PDB code:
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D.Catarzi,
V.Colotta,
and
F.Varano
(2007).
Competitive AMPA receptor antagonists.
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Med Res Rev,
27,
239-278.
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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,
and
J.S.Kastrup
(2007).
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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J Biol Chem,
282,
25726-25736.
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PDB codes:
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P.Naur,
K.B.Hansen,
A.S.Kristensen,
S.M.Dravid,
D.S.Pickering,
L.Olsen,
B.Vestergaard,
J.Egebjerg,
M.Gajhede,
S.F.Traynelis,
and
J.S.Kastrup
(2007).
Ionotropic glutamate-like receptor delta2 binds D-serine and glycine.
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Proc Natl Acad Sci U S A,
104,
14116-14121.
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PDB codes:
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K.Cohen-Kashi Malina,
Y.Ganor,
M.Levite,
and
V.I.Teichberg
(2006).
Autoantibodies against an extracellular peptide of the GluR3 subtype of AMPA receptors activate both homomeric and heteromeric AMPA receptor channels.
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Neurochem Res,
31,
1181-1190.
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P.E.Chen,
and
D.J.Wyllie
(2006).
Pharmacological insights obtained from structure-function studies of ionotropic glutamate receptors.
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Br J Pharmacol,
147,
839-853.
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U.Pentikäinen,
L.Settimo,
M.S.Johnson,
and
O.T.Pentikäinen
(2006).
Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding.
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Org Biomol Chem,
4,
1058-1070.
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B.B.Nielsen,
D.S.Pickering,
J.R.Greenwood,
L.Brehm,
M.Gajhede,
A.Schousboe,
and
J.S.Kastrup
(2005).
Exploring the GluR2 ligand-binding core in complex with the bicyclical AMPA analogue (S)-4-AHCP.
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FEBS J,
272,
1639-1648.
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PDB code:
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M.L.Mayer
(2005).
Glutamate receptor ion channels.
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Curr Opin Neurobiol,
15,
282-288.
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M.M.Holm,
M.L.Lunn,
S.F.Traynelis,
J.S.Kastrup,
and
J.Egebjerg
(2005).
Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2.
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Proc Natl Acad Sci U S A,
102,
12053-12058.
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M.M.Holm,
P.Naur,
B.Vestergaard,
M.T.Geballe,
M.Gajhede,
J.S.Kastrup,
S.F.Traynelis,
and
J.Egebjerg
(2005).
A binding site tyrosine shapes desensitization kinetics and agonist potency at GluR2. A mutagenic, kinetic, and crystallographic study.
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J Biol Chem,
280,
35469-35476.
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PDB code:
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N.A.Dorofeeva,
D.B.Tikhonov,
O.I.Barygin,
T.B.Tikhonova,
Y.I.Salnikov,
and
L.G.Magazanik
(2005).
Action of extracellular divalent cations on native alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors.
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J Neurochem,
95,
1704-1712.
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K.Strømgaard,
and
I.Mellor
(2004).
AMPA receptor ligands: synthetic and pharmacological studies of polyamines and polyamine toxins.
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Med Res Rev,
24,
589-620.
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M.Kubo,
and
E.Ito
(2004).
Structural dynamics of an ionotropic glutamate receptor.
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Proteins,
56,
411-419.
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M.L.Mayer,
and
N.Armstrong
(2004).
Structure and function of glutamate receptor ion channels.
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Annu Rev Physiol,
66,
161-181.
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M.S.Horning,
and
M.L.Mayer
(2004).
Regulation of AMPA receptor gating by ligand binding core dimers.
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Neuron,
41,
379-388.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
