5JTY

Glutamate- and DCKA-bound GluN1/GluN2A agonist binding domains with MPX-007

5JTY の概要

• エントリーDOI: 10.2210/pdb5jty/pdb
• 関連するPDBエントリー: 5I57 5I58 5I59
• 分子名称: Glutamate receptor ionotropic, NMDA 1,Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A,Glutamate receptor ionotropic, NMDA 2A, 4-hydroxy-5,7-dimethylquinoline-2-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: nmda receptor, antagonist, transport protein, receptor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : P35439 Q00959
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65690.92

構造登録者

Mou, T.-C.,Sprang, S.R.,Hansen, K.B. (登録日: 2016-05-10, 公開日: 2016-09-21, 最終更新日: 2024-10-23)

主引用文献

Yi, F.,Mou, T.C.,Dorsett, K.N.,Volkmann, R.A.,Menniti, F.S.,Sprang, S.R.,Hansen, K.B.
Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors.
Neuron, 91:1316-1329, 2016

PubMed Abstract: NMDA receptors mediate excitatory synaptic transmission and regulate synaptic plasticity in the central nervous system, but their dysregulation is also implicated in numerous brain disorders. Here, we describe GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing the apo state of the GluN1 ligand-binding domain (LBD), which is incapable of triggering channel gating. We describe structural determinants of NAM binding in crystal structures of the GluN1/2A LBD heterodimer, and analyses of NAM-bound LBD structures corresponding to active and inhibited receptor states reveal a molecular switch in the modulatory binding site that mediate the allosteric inhibition. NAM binding causes displacement of a valine in GluN2A and the resulting steric effects can be mitigated by the transition from glycine bound to apo state of the GluN1 LBD. This work provides mechanistic insight to allosteric NMDA receptor inhibition, thereby facilitating the development of novel classes NMDA receptor modulators as therapeutic agents.

PubMed: 27618671
DOI: 10.1016/j.neuron.2016.08.014

実験手法

X-RAY DIFFRACTION (2.72 Å)