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PDBsum entry 3b6t
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Membrane protein
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PDB id
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3b6t
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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 single-Channel results indicate that the rates of ligand binding domain closing and opening directly impact ampa receptor gating.
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Authors
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W.Zhang,
Y.Cho,
E.Lolis,
J.R.Howe.
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Ref.
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J Neurosci, 2008,
28,
932-943.
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PubMed id
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Abstract
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At most excitatory central synapses, glutamate is released from presynaptic
terminals and binds to postsynaptic AMPA receptors, initiating a series of
conformational changes that result in ion channel opening. Efficient
transmission at these synapses requires that glutamate binding to AMPA receptors
results in rapid and near-synchronous opening of postsynaptic receptor channels.
In addition, if the information encoded in the frequency of action potential
discharge is to be transmitted faithfully, glutamate must dissociate from the
receptor quickly, enabling the synapse to discriminate presynaptic action
potentials that are spaced closely in time. The current view is that the
efficacy of agonists is directly related to the extent to which ligand binding
results in closure of the binding domain. For glutamate to dissociate from the
receptor, however, the binding domain must open. Previously, we showed that
mutations in glutamate receptor subunit 2 that should destabilize the closed
conformation not only sped deactivation but also altered the relative efficacy
of glutamate and quisqualate. Here we present x-ray crystallographic and
single-channel data that support the conclusions that binding domain closing
necessarily precedes channel opening and that the kinetics of conformational
changes at the level of the binding domain importantly influence ion channel
gating. Our findings suggest that the stability of the closed-cleft conformation
has been tuned during evolution so that glutamate dissociates from the receptor
as rapidly as possible but remains an efficacious agonist.
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Secondary reference #1
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Title
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Tuning activation of the ampa-Sensitive glur2 ion channel by genetic adjustment of agonist-Induced conformational changes.
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Authors
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N.Armstrong,
M.Mayer,
E.Gouaux.
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Ref.
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Proc Natl Acad Sci U S A, 2003,
100,
5736-5741.
[DOI no: ]
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PubMed id
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Figure 4.
Fig. 4. Comparison of WT and S1S2J L650T/AMPA(AS)
conformations. (A) Superposition of WT S1S2J/AMPA (gray) with
S1S2J L650T/AMPA (AS form) protomer A (blue). (B) Superposition
of WT S1S2J/AMPA (gray) with S1S2J L650T/AMPA(AS) protomer B
(green). The black arrows in A and B indicate the axis of
rotation relating the conformational difference between the WT
and L650T structures. (C) Superimposed WT and mutant AMPA dimers.
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Figure 6.
Fig. 6. Mechanism of agonist binding and domain closure.
(A) The binding site of the open-cleft, closed-channel state
(Apo S1S2J, protomer A). (B) The possible first step in agonist
binding as observed in molecule B of the L650T/AMPA(AS)
structure. We suggest that this semiclosed cleft conformation
represents the agonist-bound, closed-channel state. (C) The
closed-cleft, open-channel conformation as observed in the WT
S1S2J/AMPA binding cleft (protomer A). In B and C, water
molecules are shown as green spheres, AMPA is drawn in magenta,
and hydrogen bonds are depicted by black dashed lines. The
degrees of domain closure relative to the Apo conformation are
indicated below each structure.
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