7Y7Z

Cryo-EM structure of human GABA transporter GAT1 bound with tiagabine in NaCl solution in an inward-open state at 3.2 angstrom

7Y7Z の概要

• エントリーDOI: 10.2210/pdb7y7z/pdb
• 関連するPDBエントリー: 7Y7V 7Y7W 7Y7X 7Y7Y
• EMDBエントリー: 33671 33672 33673 33674 33675
• 分子名称: Sodium- and chloride-dependent GABA transporter 1, Tiagabine, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: gaba transporter, gat1, nipecotic acid, tiagabine, neurotransmitter, slc6a1, 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: 71970.52

構造登録者

Zhu, A.,Huang, J.,Kong, F.,Tan, J.,Lei, J.,Yuan, Y.,Yan, C. (登録日: 2022-06-22, 公開日: 2023-04-26, 最終更新日: 2024-10-23)

主引用文献

Zhu, A.,Huang, J.,Kong, F.,Tan, J.,Lei, J.,Yuan, Y.,Yan, C.
Molecular basis for substrate recognition and transport of human GABA transporter GAT1.
Nat.Struct.Mol.Biol., 30:1012-1022, 2023

PubMed Abstract: γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2-3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine.

PubMed: 37400655
DOI: 10.1038/s41594-023-00983-z

実験手法

ELECTRON MICROSCOPY (3.2 Å)