9LK7

Cryo-EM Structure of GAT3

9LK7 の概要

• エントリーDOI: 10.2210/pdb9lk7/pdb
• EMDBエントリー: 63170
• 分子名称: Sodium- and chloride-dependent GABA transporter 3 (1 entity in total)
• 機能のキーワード: protein structure, structural protein, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70628.31

構造登録者

Zhao, Y.,Xu, H. (登録日: 2025-01-16, 公開日: 2025-08-20, 最終更新日: 2026-03-04)

主引用文献

Xu, H.,Zhang, Y.,Bai, Q.,He, L.,Chen, Q.,Qiu, Y.,Li, R.,Yu, J.,Zhao, J.,Zhao, Y.
Substrate and inhibitor binding of human GABA transporter 3.
Structure, 33:2049-2057.e5, 2025

PubMed Abstract: GABA (g-aminobutyric acid) transporter 3 (GAT3) is primarily found in glial cells and is essential for regulating GABA homeostasis in the central nervous system by mediating GABA uptake. Consequently, GAT3 has emerged as a significant therapeutic target for the treatment of epilepsy. In this study, we present the cryoelectron microscopy (cryo-EM) structures of GAT3 bound to its substrate GABA, the selective inhibitor SNAP-5114, and in the substrate-free state. GAT3 binds to GABA in an inward-facing conformation, while SNAP-5114 occupies the GABA-binding pocket and is stabilized by extensive interactions with surrounding residues. Functional studies reveal that E66 plays a pivotal role in determining the substrate-binding mode and specificity of SNAP-5114 binding. Taken together, our study clarifies the GABA binding mechanism of GAT3 and reveals the molecular basis for the specific inhibition of SNAP-5114, offering valuable insights for developing GAT3 subtypes selective inhibitors, which hold potential as a treatment for epilepsy.

PubMed: 40914153
DOI: 10.1016/j.str.2025.08.012

実験手法

ELECTRON MICROSCOPY (3.6 Å)