8SSA

Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state)

8SSA の概要

• エントリーDOI: 10.2210/pdb8ssa/pdb
• EMDBエントリー: 40749
• 分子名称: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera, Protein cornichon homolog 2, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (5 entities in total)
• 機能のキーワード: ampa receptor, spermidine, tarp gamma-5, cornichon-2, signaling protein
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 507991.49

構造登録者

Gangwar, S.P.,Yen, L.Y.,Yelshanskaya, M.V.,Sobolevsky, A.I. (登録日: 2023-05-08, 公開日: 2023-09-06, 最終更新日: 2024-11-06)

主引用文献

Gangwar, S.P.,Yen, L.Y.,Yelshanskaya, M.V.,Korman, A.,Jones, D.R.,Sobolevsky, A.I.
Modulation of GluA2-gamma 5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2.
Nat.Struct.Mol.Biol., 30:1481-1494, 2023

PubMed Abstract: Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.

PubMed: 37653241
DOI: 10.1038/s41594-023-01080-x

実験手法

ELECTRON MICROSCOPY (3.88 Å)