9OOT

Pre-active state of Gly/Glu/Pregnenolone Sulfate bound hGluN1a-2B NMDAR

9OOT の概要

• エントリーDOI: 10.2210/pdb9oot/pdb
• EMDBエントリー: 70672
• 分子名称: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, GLYCINE, ... (6 entities in total)
• 機能のキーワード: n-methyl-d-aspartate receptor, pre-active, glun2b, pregnenolone sulfate, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 384157.09

構造登録者

Hyunook, K.,Hiro, F. (登録日: 2025-05-16, 公開日: 2025-10-29, 最終更新日: 2025-12-17)

主引用文献

Kang, H.,Steigerwald, R.,Ullman, E.Z.,Epstein, M.,Paladugu, S.,Liotta, D.C.,Traynelis, S.F.,Furukawa, H.
Mechanism of conductance control and neurosteroid binding in NMDA receptors.
Nature, 648:220-228, 2025

PubMed Abstract: Ion-channel activity reflects a combination of open probability and unitary conductance. Many channels display subconductance states that modulate signalling strength, yet the structural mechanisms governing conductance levels remain incompletely understood. Here we report that conductance levels are controlled by the bending patterns of pore-forming transmembrane helices in the heterotetrameric neuronal channel GluN1a-2B N-methyl-D-aspartate receptor (NMDAR). Our single-particle electron cryomicroscopy (cryo-EM) analyses demonstrate that an endogenous neurosteroid and synthetic positive allosteric modulator (PAM), 24S-hydroxycholesterol (24S-HC), binds to a juxtamembrane pocket in the GluN2B subunit and stabilizes the fully open-gate conformation, where GluN1a M3 and GluN2B M3' pore-forming helices are bent to dilate the channel pore. By contrast, EU1622-240 binds to the same GluN2B juxtamembrane pocket and a distinct juxtamembrane pocket in GluN1a to stabilize a sub-open state whereby only the GluN2B M3' helix is bent. Consistent with the varying extents of gate opening, the single-channel recordings predominantly show full-conductance and subconductance states in the presence of 24S-HC and EU1622-240, respectively. Another class of neurosteroid, pregnenolone sulfate, engages a similar GluN2B pocket, but two molecules bind simultaneously, revealing a diverse neurosteroid recognition pattern. Our study identifies that the juxtamembrane pockets are critical structural hubs for modulating conductance levels in NMDAR.

PubMed: 41162707
DOI: 10.1038/s41586-025-09695-4

実験手法

ELECTRON MICROSCOPY (3.13 Å)