2AL4

CRYSTAL STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH quisqualate and CX614.

Summary for 2AL4

• Entry DOI: 10.2210/pdb2al4/pdb
• Related: 1LBC 1MM6 1MM7 2AL5
• Descriptor: Glutamate receptor 2, ZINC ION, (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID, ... (5 entities in total)
• Functional Keywords: ionotropic glutamate receptor, glur2, ligand binding core, s1s2, quisqualate, cx614, modulator, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 6
• Total formula weight: 177860.68

Authors

Jin, R.,Clark, S.,Weeks, A.M.,Dudman, J.T.,Gouaux, E.,Partin, K.M. (deposition date: 2005-08-04, release date: 2005-10-25, Last modification date: 2024-11-13)

Primary citation

Jin, R.,Clark, S.,Weeks, A.M.,Dudman, J.T.,Gouaux, E.,Partin, K.M.
Mechanism of positive allosteric modulators acting on AMPA receptors.
J.Neurosci., 25:9027-9036, 2005

PubMed 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.

PubMed: 16192394
DOI: 10.1523/JNEUROSCI.2567-05.2005

Experimental method

X-RAY DIFFRACTION (1.7 Å)