PDBsum entry 3kei

Transport protein

PDB id: 3kei

Contents

Protein chains

257 a.a. *

Ligands

GLU ×2

Waters ×270

* Residue conservation analysis

PDB id:

3kei

Name:

Transport protein

Title:

Crystal structure of the glua4 ligand-binding domain l651v mutant in complex with glutamate

Structure:

Glutamate receptor 4. Chain: a, b. Fragment: ligand binding domain. Synonym: glur-4, glur4, glur-d, glutamate receptor ionotropic, ampa 4, ampa-selective glutamate receptor 4. Engineered: yes. Mutation: yes

Source:

Rattus norvegicus. Brown rat,rat,rats. Organism_taxid: 10116. Strain: sprague-dawley. Gene: glur4, gria4. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.205 R-free: 0.224

Authors:

A.Gill,D.R.Madden

Key ref:

A.Birdsey-Benson et al. (2010). Enhanced efficacy without further cleft closure: reevaluating twist as a source of agonist efficacy in AMPA receptors. J Neurosci, 30, 1463-1470. PubMed id: 20107073

Date:

26-Oct-09 Release date: 09-Feb-10

Protein chains

P19493  (GRIA4_RAT) -  Glutamate receptor 4 from Rattus norvegicus

Seq: 902 a.a.

Struc: 257 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

J Neurosci 30:1463-1470 (2010)

PubMed id: 20107073

Enhanced efficacy without further cleft closure: reevaluating twist as a source of agonist efficacy in AMPA receptors.

A.Birdsey-Benson, A.Gill, L.P.Henderson, D.R.Madden.

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.