2al4
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CRYSTAL STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH quisqualate and CX614.
OverviewOverview
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.
About this StructureAbout this Structure
2AL4 is a Single protein structure of sequence from Rattus norvegicus with ZN, CX6 and QUS as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Mechanism of positive allosteric modulators acting on AMPA receptors., Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM, J Neurosci. 2005 Sep 28;25(39):9027-36. PMID:16192394
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