4N07

Crystal structure of the GluA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and BPAM-344 at 1.87 A resolution

4N07 の概要

• エントリーDOI: 10.2210/pdb4n07/pdb
• 関連するPDBエントリー: 3tdj
• 分子名称: Glutamate receptor 2, 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, GLUTAMIC ACID, ... (8 entities in total)
• 機能のキーワード: ampa receptor ligand-binding domain, glua2 s1s2j-l483y-n754s, bpam-344 allosteric modulation, membrane protein
• 由来する生物種: Rattus norvegicus (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: 3
• 化学式量合計: 91013.45

構造登録者

Noerholm, A.B.,Frydenvang, K.,Kastrup, J.S. (登録日: 2013-10-01, 公開日: 2013-11-20, 最終更新日: 2024-11-06)

主引用文献

Nrholm, A.B.,Francotte, P.,Olsen, L.,Krintel, C.,Frydenvang, K.,Goffin, E.,Challal, S.,Danober, L.,Botez-Pop, I.,Lestage, P.,Pirotte, B.,Kastrup, J.S.
Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold.
J.Med.Chem., 56:8736-8745, 2013

PubMed Abstract: Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.

PubMed: 24131202
DOI: 10.1021/jm4012092

実験手法

X-RAY DIFFRACTION (1.87 Å)