5H8H

Structure of the human GluN1/GluN2A LBD in complex with GNE3419

5H8H の概要

• エントリーDOI: 10.2210/pdb5h8h/pdb
• 関連するPDBエントリー: 5H8F 5H8N 5H8Q 5H8R 5H8S
• 分子名称: Glutamate receptor ionotropic, NMDA 2A,Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1,Glutamate receptor ionotropic, NMDA 1, ACETATE ION, ... (8 entities in total)
• 機能のキーワード: glun1, glun2a, nmda, receptor, 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 : Q12879 Q05586
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65914.21

構造登録者

Wallweber, H.J.A.,Lupardus, P.J. (登録日: 2015-12-23, 公開日: 2016-02-24, 最終更新日: 2024-10-16)

主引用文献

Hackos, D.H.,Lupardus, P.J.,Grand, T.,Chen, Y.,Wang, T.M.,Reynen, P.,Gustafson, A.,Wallweber, H.J.,Volgraf, M.,Sellers, B.D.,Schwarz, J.B.,Paoletti, P.,Sheng, M.,Zhou, Q.,Hanson, J.E.
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
Neuron, 89:983-999, 2016

PubMed Abstract: To enhance physiological function of NMDA receptors (NMDARs), we identified positive allosteric modulators (PAMs) of NMDARs with selectivity for GluN2A subunit-containing receptors. X-ray crystallography revealed a binding site at the GluN1-GluN2A dimer interface of the extracellular ligand-binding domains (LBDs). Despite the similarity between the LBDs of NMDARs and AMPA receptors (AMPARs), GluN2A PAMs with good selectivity against AMPARs were identified. Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices from wild-type (WT), but not GluN2A knockout (KO), mice. Individual GluN2A PAMs exhibited variable degrees of glutamate (Glu) dependence, impact on NMDAR Glu EC50, and slowing of channel deactivation. These distinct PAMs also exhibited differential impacts during synaptic plasticity induction. The identification of a new NMDAR modulatory site and characterization of GluN2A-selective PAMs provide powerful molecular tools to dissect NMDAR function and demonstrate the feasibility of a therapeutically desirable type of NMDAR enhancement.

PubMed: 26875626
DOI: 10.1016/j.neuron.2016.01.016

実験手法

X-RAY DIFFRACTION (2.23 Å)