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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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References listed in PDB file
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Key reference
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Title
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Mechanism of positive allosteric modulators acting on ampa receptors.
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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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Ref.
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J Neurosci, 2005,
25,
9027-9036.
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PubMed id
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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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Secondary reference #1
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Title
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Mechanism of activation and selectivity in a ligand-Gated ion channel: structural and functional studies of glur2 and quisqualate.
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Authors
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R.Jin,
M.Horning,
M.L.Mayer,
E.Gouaux.
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Ref.
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Biochemistry, 2002,
41,
15635-15643.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Mechanism of glutamate receptor desensitization.
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Authors
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Y.Sun,
R.Olson,
M.Horning,
N.Armstrong,
M.Mayer,
E.Gouaux.
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Ref.
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Nature, 2002,
417,
245-253.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2: The L483Y mutation and CTZ stabilize the GluR2 S1S2J
dimer. a, Side view of the S1S2J -L483Y dimer in complex with
AMPA. Subunit A is grey (domain 1) and blue (domain 2). Subunit
B is pink (domain 1) and purple (domain 2). Residues from A are
cyan; residues from B are yellow. Lys 505 and Ile 633 flank
transmembrane segments 1 and 2, respectively. b, Top view of the
L483Y dimer looking down the 2-fold axis. c, CTZ stabilizes the
GluR2 S1S2J -N754S dimer by binding in the dimer interface. Side
view of the S1S2J dimer in a complex with glutamate and CTZ. The
two CTZ molecules are green and are shown in CPK representation.
d, Top view of the S1S2J-Glu -CTZ dimer, looking down the 2-fold
axis. e, Interactions between Tyr 483 from one subunit and Leu
748 and Lys 752 from another subunit. Similar interactions also
occur in the dimer of S1S2J -L483Y in complex with DNQX. Note
the intersubunit hydrogen bond between Asn 754 and the carbonyl
oxygen of Ser 729. f, Interactions between CTZ and residues from
subunits A (cyan) and B (yellow). The black dashed lines are
hydrogen bonds and the light blue spheres are water molecules.
Stereoviews of e and f are provided in Supplementary Information.
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Figure 5.
Figure 5: Agonist-induced conformational changes in the dimer
and gating model. a, Overlap of the S1S2J -L483Y dimers bound
with either an agonist (AMPA, green) or an antagonist (DNQX,
red). The relative movement of the linker region, which connects
the ligand-binding core to the channel-forming segments, is
represented by the difference in position of Ile 633 in the two
structures. Distances between Ile 633 on two protomers are 28.3
Å in the DNQX structure and 36.3 Å in the AMPA structure. In
addition, Ile 633 rotates around the 2-fold axis by 1.25° and
moves 2.5 Å along the 2-fold axis, away from the membrane. b, A
model for glutamate receptor activation and desensitization.
Domain 1 and domain 2 of the ligand-binding core are labelled D1
and D2, respectively. Transmembrane segments of each subunit are
indicated by a single green cylinder and the N-terminal domain
(ATD) has not been included in the model. Each subunit binds a
single agonist (A, red circle) and exists in three distinct
conformations: closed (C), open (O) and desensitized (D). The
closed and open states share the same S1S2 dimer interface.
After the binding of agonist, closure of domain 2 towards domain
1 opens the channel gate, whereas closure of domain 1 towards
domain 2 disrupts the dimer interface and desensitizes the
receptor. The states are connected by using a simplified model
for activation and desensitization, more complex versions of
which quantitatively describe AMPA receptor responses10,25. A
hypothetical plot of the free-energy change occurring during
activation and desensitization is shown in the lower left panel
for the wild-type (black line), L483Y (green line) and S754D
(red line) species.
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The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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