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PDBsum entry 2al4
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Membrane protein
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PDB id
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2al4
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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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Crystal structure of the glur2 ligand binding core (s1s2j) in complex with quisqualate and cx614.
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Structure:
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Glutamate receptor 2. Chain: a, b, c, d, e, f. Fragment: ligand binding core (s1s2j). Synonym: glur-2, glur-b, glur-k2, glutamate receptor ionotropic, ampa 2. Engineered: yes. Mutation: yes
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Source:
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Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli. 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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1.70Å
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R-factor:
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0.209
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R-free:
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0.223
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Authors:
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R.Jin,S.Clark,A.M.Weeks,J.T.Dudman,E.Gouaux,K.M.Partin
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Key ref:
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R.Jin
et al.
(2005).
Mechanism of positive allosteric modulators acting on AMPA receptors.
J Neurosci,
25,
9027-9036.
PubMed id:
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Date:
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04-Aug-05
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Release date:
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25-Oct-05
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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.
258 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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J Neurosci
25:9027-9036
(2005)
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PubMed id:
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Mechanism of positive allosteric modulators acting on AMPA receptors.
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R.Jin,
S.Clark,
A.M.Weeks,
J.T.Dudman,
E.Gouaux,
K.M.Partin.
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ABSTRACT
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Ligand-gated ion channels involved in the modulation of synaptic strength are
the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate
AMPA receptor currents relieve cognitive deficits caused by neurodegenerative
diseases such as Alzheimer's disease and show promise in the treatment of
depression. Previously, there has been limited understanding of the molecular
mechanism of action for AMPA receptor potentiators. Here we present cocrystal
structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex
with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614
(pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor
potentiators that preferentially slow AMPA receptor deactivation. Both
potentiators bind within the dimer interface of the nondesensitized receptor at
a common site located on the twofold axis of molecular symmetry. Importantly,
the potentiator binding site is adjacent to the "hinge" in the ligand-binding
core "clamshell" that undergoes conformational rearrangement after glutamate
binding. Using rapid solution exchange, patch-clamp electrophysiology
experiments, we show that point mutations of residues that interact with
potentiators in the cocrystal disrupt potentiator function. We suggest that the
potentiators slow deactivation by stabilizing the clamshell in its closed-cleft,
glutamate-bound conformation.
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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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S.S.Cha,
Y.J.An,
C.S.Jeong,
M.K.Kim,
S.G.Lee,
K.H.Lee,
and
B.H.Oh
(2012).
Experimental phasing using zinc anomalous scattering.
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Acta Crystallogr D Biol Crystallogr,
68,
1253-1258.
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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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K.M.Vance,
N.Simorowski,
S.F.Traynelis,
and
H.Furukawa
(2011).
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors.
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Nat Commun,
2,
294.
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PDB codes:
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M.L.Mayer
(2011).
Glutamate receptor ion channels: where do all the calories go?
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Nat Struct Mol Biol,
18,
253-254.
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M.Sukumaran,
M.Rossmann,
I.Shrivastava,
A.Dutta,
I.Bahar,
and
I.H.Greger
(2011).
Dynamics and allosteric potential of the AMPA receptor N-terminal domain.
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EMBO J,
30,
972-982.
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PDB codes:
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A.H.Ahmed,
C.P.Ptak,
and
R.E.Oswald
(2010).
Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA.
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Biochemistry,
49,
2843-2850.
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PDB codes:
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A.H.Ahmed,
and
R.E.Oswald
(2010).
Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.
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J Med Chem,
53,
2197-2203.
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PDB codes:
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A.R.Lorier,
G.D.Funk,
and
J.J.Greer
(2010).
Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy.
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PLoS One,
5,
e8766.
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C.Cepeda,
D.M.Cummings,
M.A.Hickey,
M.Kleiman-Weiner,
J.Y.Chen,
J.B.Watson,
and
M.S.Levine
(2010).
Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.
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PLoS Curr,
2,
0.
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M.L.Prieto,
and
L.P.Wollmuth
(2010).
Gating modes in AMPA receptors.
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J Neurosci,
30,
4449-4459.
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S.E.Ward,
B.D.Bax,
and
M.Harries
(2010).
Challenges for and current status of research into positive modulators of AMPA receptors.
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Br J Pharmacol,
160,
181-190.
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A.I.Sobolevsky,
M.P.Rosconi,
and
E.Gouaux
(2009).
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
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Nature,
462,
745-756.
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PDB codes:
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A.J.Plested,
and
M.L.Mayer
(2009).
Engineering a high-affinity allosteric binding site for divalent cations in kainate receptors.
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Neuropharmacology,
56,
114-120.
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C.Chaudhry,
A.J.Plested,
P.Schuck,
and
M.L.Mayer
(2009).
Energetics of glutamate receptor ligand binding domain dimer assembly are modulated by allosteric ions.
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Proc Natl Acad Sci U S A,
106,
12329-12334.
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C.P.Ptak,
A.H.Ahmed,
and
R.E.Oswald
(2009).
Probing the allosteric modulator binding site of GluR2 with thiazide derivatives.
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Biochemistry,
48,
8594-8602.
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PDB codes:
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D.Berezhnoy,
T.T.Gibbs,
and
D.H.Farb
(2009).
Docking of 1,4-benzodiazepines in the alpha1/gamma2 GABA(A) receptor modulator site.
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Mol Pharmacol,
76,
440-450.
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H.Yuan,
K.B.Hansen,
K.M.Vance,
K.K.Ogden,
and
S.F.Traynelis
(2009).
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
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J Neurosci,
29,
12045-12058.
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K.B.Hansen,
P.Naur,
N.L.Kurtkaya,
A.S.Kristensen,
M.Gajhede,
J.S.Kastrup,
and
S.F.Traynelis
(2009).
Modulation of the dimer interface at ionotropic glutamate-like receptor delta2 by D-serine and extracellular calcium.
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J Neurosci,
29,
907-917.
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K.E.Montgomery,
M.Kessler,
and
A.C.Arai
(2009).
Modulation of agonist binding to AMPA receptors by 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546): differential effects across brain regions and GluA1-4/transmembrane AMPA receptor regulatory protein combinations.
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J Pharmacol Exp Ther,
331,
965-974.
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M.Baudry
(2009).
Multi-level control of ionotropic glutamate receptor function.
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Cellscience,
6,
79.
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S.M.Schmid,
S.Kott,
C.Sager,
T.Huelsken,
and
M.Hollmann
(2009).
The glutamate receptor subunit delta2 is capable of gating its intrinsic ion channel as revealed by ligand binding domain transplantation.
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Proc Natl Acad Sci U S A,
106,
10320-10325.
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X.W.Su,
X.Y.Li,
M.Banasr,
J.W.Koo,
M.Shahid,
B.Henry,
and
R.S.Duman
(2009).
Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus.
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Psychopharmacology (Berl),
206,
215-222.
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A.D.Milstein,
and
R.A.Nicoll
(2008).
Regulation of AMPA receptor gating and pharmacology by TARP auxiliary subunits.
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Trends Pharmacol Sci,
29,
333-339.
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C.A.Zarate,
and
H.K.Manji
(2008).
The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases.
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Exp Neurol,
211,
7.
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C.R.Yang,
and
K.A.Svensson
(2008).
Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia.
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Pharmacol Ther,
120,
317-332.
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J.Vaglenova,
N.Pandiella,
N.Wijayawardhane,
T.Vaithianathan,
S.Birru,
C.Breese,
V.Suppiramaniam,
and
C.Randal
(2008).
Aniracetam reversed learning and memory deficits following prenatal ethanol exposure by modulating functions of synaptic AMPA receptors.
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Neuropsychopharmacology,
33,
1071-1083.
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L.A.Cruz,
E.Estébanez-Perpiñá,
S.Pfaff,
S.Borngraeber,
N.Bao,
J.Blethrow,
R.J.Fletterick,
and
P.M.England
(2008).
6-Azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX) forms an irreversible bond to the active site of the GluR2 AMPA receptor.
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J Med Chem,
51,
5856-5860.
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PDB code:
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M.Kessler,
E.Suzuki,
K.Montgomery,
and
A.C.Arai
(2008).
Physiological significance of high- and low-affinity agonist binding to neuronal and recombinant AMPA receptors.
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Neurochem Int,
52,
1383-1393.
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R.Raabe,
and
L.Gentile
(2008).
Antidepressant interactions with the NMDA NR1-1b subunit.
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J Biophys,
2008,
474205.
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Y.Yao,
C.B.Harrison,
P.L.Freddolino,
K.Schulten,
and
M.L.Mayer
(2008).
Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors.
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EMBO J,
27,
2158-2170.
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PDB codes:
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A.J.Plested,
and
M.L.Mayer
(2007).
Structure and mechanism of kainate receptor modulation by anions.
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Neuron,
53,
829-841.
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PDB code:
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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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N.A.Mitchell,
and
M.W.Fleck
(2007).
Targeting AMPA receptor gating processes with allosteric modulators and mutations.
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Biophys J,
92,
2392-2402.
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A.Priel,
S.Selak,
J.Lerma,
and
Y.Stern-Bach
(2006).
Block of kainate receptor desensitization uncovers a key trafficking checkpoint.
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Neuron,
52,
1037-1046.
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A.S.Kristensen,
M.T.Geballe,
J.P.Snyder,
and
S.F.Traynelis
(2006).
Glutamate receptors: variation in structure-function coupling.
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Trends Pharmacol Sci,
27,
65-69.
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C.Prescott,
A.M.Weeks,
K.J.Staley,
and
K.M.Partin
(2006).
Kynurenic acid has a dual action on AMPA receptor responses.
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Neurosci Lett,
402,
108-112.
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G.Lynch,
and
C.M.Gall
(2006).
Ampakines and the threefold path to cognitive enhancement.
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Trends Neurosci,
29,
554-562.
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M.C.Weston,
P.Schuck,
A.Ghosal,
C.Rosenmund,
and
M.L.Mayer
(2006).
Conformational restriction blocks glutamate receptor desensitization.
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Nat Struct Mol Biol,
13,
1120-1127.
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PDB codes:
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M.L.Mayer
(2006).
Glutamate receptors at atomic resolution.
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Nature,
440,
456-462.
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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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S.Tomita,
M.Sekiguchi,
K.Wada,
R.A.Nicoll,
and
D.S.Bredt
(2006).
Stargazin controls the pharmacology of AMPA receptor potentiators.
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Proc Natl Acad Sci U S A,
103,
10064-10067.
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H.Furukawa,
S.K.Singh,
R.Mancusso,
and
E.Gouaux
(2005).
Subunit arrangement and function in NMDA receptors.
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Nature,
438,
185-192.
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PDB codes:
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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
