8VJ7

GluA2 bound to GYKI-52466 and Glutamate, Inhibited State 2

これはPDB形式変換不可エントリーです。

8VJ7 の概要

• エントリーDOI: 10.2210/pdb8vj7/pdb
• EMDBエントリー: 43276
• 分子名称: Isoform Flip of Glutamate receptor 2, GLUTAMIC ACID, 4-[(5S,8R)-8-methyl-6,7,8,9-tetrahydro-2H,5H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-5-yl]aniline (3 entities in total)
• 機能のキーワード: ligand gated ion channel, ionotropic glutamate receptor, allosteric inhibition, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 358693.64

構造登録者

Hale, W.D.,Montano Romero, A.,Huganir, R.L.,Twomey, E.C. (登録日: 2024-01-05, 公開日: 2024-06-05, 最終更新日: 2025-05-28)

主引用文献

Hale, W.D.,Montano Romero, A.,Gonzalez, C.U.,Jayaraman, V.,Lau, A.Y.,Huganir, R.L.,Twomey, E.C.
Allosteric competition and inhibition in AMPA receptors.
Nat.Struct.Mol.Biol., 31:1669-1679, 2024

PubMed Abstract: Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases.

PubMed: 38834914
DOI: 10.1038/s41594-024-01328-0

実験手法

ELECTRON MICROSCOPY (4.85 Å)