9OOP

Human delta 2 receptor with R710W Cerebellar Ataxia mutation in the apo leak state

9OOP の概要

• エントリーDOI: 10.2210/pdb9oop/pdb
• EMDBエントリー: 70668
• 分子名称: Human delta 2 receptor with R710W Cerebellar Ataxia mutation (1 entity in total)
• 機能のキーワード: ligand-gated ion channel, ion channel, neurotransmitter receptor, transport protein
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 321452.12

構造登録者

Wang, H.,Ahmed, F.,Khau, J.,Mondal, A.K.,Twomey, E.C. (登録日: 2025-05-16, 公開日: 2025-09-24, 最終更新日: 2025-12-10)

主引用文献

Wang, H.,Ahmed, F.,Khau, J.,Mondal, A.K.,Twomey, E.C.
Delta-type glutamate receptors are ligand-gated ion channels.
Nature, 647:1063-1071, 2025

PubMed Abstract: Delta-type ionotropic glutamate receptors (iGluRs, also known as GluDs) are members of the iGluR ligand-gated ion channel family, yet their function remains unknown. Although GluDs are widely expressed in the brain, have key roles in synaptic organization, and harbour disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed. Here we define GluDs as ligand-gated ion channels that are tightly regulated in cellular contexts by purifying human GluD2 (hGluD2) and directly characterizing its structure and function using cryo-electron microscopy and bilayer recordings. We show that hGluD2 is activated by D-serine and GABA (γ-aminobutyric acid), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains, which are coordinated by the amino-terminal domain above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the ligand-binding domain rearranges the receptor architecture and induces leak currents. Our findings demonstrate that GluDs possess the intrinsic biophysical properties of ligand-gated ion channels, reconciling prior conflicting observations to establish a framework for understanding their cellular regulation and for developing therapies targeting GluD2.

PubMed: 40957579
DOI: 10.1038/s41586-025-09610-x

実験手法

ELECTRON MICROSCOPY (3.73 Å)