2AL4: Crystal Structure Of The Glur2 Ligand Binding Core (s1s2j) In Complex With Quisqualate And Cx614

Citation:
Abstract
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.
PDB ID: 2AL4Download
MMDB ID: 35625
PDB Deposition Date: 2005/8/4
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 2AL4: trimeric; determined by software (PISA)
Molecular Components in 2AL4
Label Count Molecule
Proteins (3 molecules)
3
Glutamate Receptor 2(Gene symbol: Gria2)
Molecule annotation
Chemicals (11 molecules)
1
5
2
3
3
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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