3KFM

Crystal Structure of the GluA4 Ligand-Binding domain L651V mutant in complex with kainate

Summary for 3KFM

• Entry DOI: 10.2210/pdb3kfm/pdb
• Related: 3KEI
• Descriptor: Glutamate receptor 4, 3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE (3 entities in total)
• Functional Keywords: glua4, ampa receptor, ligand-gated ion channel, ligand-binding domain, l651v, kainate, alternative splicing, cell junction, cell membrane, glycoprotein, ion transport, ionic channel, lipoprotein, membrane, palmitate, postsynaptic cell membrane, receptor, synapse, transmembrane, transport, transport protein
• Biological source: Rattus norvegicus (brown rat,rat,rats); More
• Total number of polymer chains: 1
• Total formula weight: 28936.40

Authors

Gill, A.,Madden, D.R. (deposition date: 2009-10-27, release date: 2010-02-09, Last modification date: 2023-09-06)

Primary citation

Birdsey-Benson, A.,Gill, A.,Henderson, L.P.,Madden, D.R.
Enhanced efficacy without further cleft closure: reevaluating twist as a source of agonist efficacy in AMPA receptors.
J.Neurosci., 30:1463-1470, 2010

PubMed Abstract: 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.

PubMed: 20107073
DOI: 10.1523/JNEUROSCI.4558-09.2010

Experimental method

X-RAY DIFFRACTION (2.2 Å)