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PDBsum entry 3kfm
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Transport protein
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PDB id
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3kfm
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References listed in PDB file
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Key reference
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Title
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Enhanced efficacy without further cleft closure: reevaluating twist as a source of agonist efficacy in ampa receptors.
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Authors
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A.Birdsey-Benson,
A.Gill,
L.P.Henderson,
D.R.Madden.
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Ref.
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J Neurosci, 2010,
30,
1463-1470.
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PubMed id
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Abstract
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AMPA receptors (AMPARs) are tetrameric ligand-gated ion channels that couple the
energy of glutamate binding to the opening of a transmembrane channel.
Crystallographic and electrophysiological analysis of AMPARs has suggested a
coupling between (1) cleft closure in the bilobate ligand-binding domain (LBD),
(2) the resulting separation of transmembrane helix attachment points across
subunit dimers, and (3) agonist efficacy. In general, more efficacious agonists
induce greater degrees of cleft closure and transmembrane separation than
partial agonists. Several apparent violations of the cleft-closure/efficacy
paradigm have emerged, although in all cases, intradimer separation remains as
the driving force for channel opening. Here, we examine the structural basis of
partial agonism in GluA4 AMPARs. We find that the L651V substitution enhances
the relative efficacy of kainate without increasing either LBD cleft closure or
transmembrane separation. Instead, the conformational change relative to the
wild-type:kainate complex involves a twisting motion with the efficacy
contribution opposite from that expected based on previous analyses. As a
result, channel opening may involve transmembrane rearrangements with a
significant rotational component. Furthermore, a two-dimensional analysis of
agonist-induced GluA2 LBD motions suggests that efficacy is not a linearly
varying function of lobe 2 displacement vectors, but is rather determined by
specific conformational requirements of the transmembrane domains.
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