3RN8

Crystal Structure of iGluR2 Ligand Binding Domain and Symmetrical Carboxyl Containing Potentiator

3RN8 の概要

• エントリーDOI: 10.2210/pdb3rn8/pdb
• 関連するPDBエントリー: 1FTJ 1FTK 1FTL 1LB9 1LBC 3RNN
• 分子名称: Glutamate receptor 2, GLUTAMIC ACID, 3,3'-benzene-1,4-diylbis(4-cyano-5-ethylthiophene-2-carboxylic acid), ... (7 entities in total)
• 機能のキーワード: glutamate receptor potentiator complex, ligand gated ion channel, membrane, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : P42262
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 94596.11

構造登録者

Timm, D.E. (登録日: 2011-04-22, 公開日: 2011-05-25, 最終更新日: 2024-11-06)

主引用文献

Timm, D.E.,Benveniste, M.,Weeks, A.M.,Nisenbaum, E.S.,Partin, K.M.
Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation.
Mol.Pharmacol., 80:267-280, 2011

PubMed Abstract: At the dimer interface of the extracellular ligand-binding domain of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously.

PubMed: 21543522
DOI: 10.1124/mol.110.070243

実験手法

X-RAY DIFFRACTION (1.7 Å)