2AL4

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

2AL4 の概要

• エントリーDOI: 10.2210/pdb2al4/pdb
• 関連するPDBエントリー: 1LBC 1MM6 1MM7 2AL5
• 分子名称: Glutamate receptor 2, ZINC ION, (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID, ... (5 entities in total)
• 機能のキーワード: ionotropic glutamate receptor, glur2, ligand binding core, s1s2, quisqualate, cx614, modulator, membrane protein
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: P19491
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 177860.68

構造登録者

Jin, R.,Clark, S.,Weeks, A.M.,Dudman, J.T.,Gouaux, E.,Partin, K.M. (登録日: 2005-08-04, 公開日: 2005-10-25, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)