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TitleMolecular basis for substrate recognition and transport of human GABA transporter GAT1.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 7, Page 1012-1022, Year 2023
Publish dateJul 3, 2023
AuthorsAngqi Zhu / Junhao Huang / Fang Kong / Jiaxin Tan / Jianlin Lei / Yafei Yuan / Chuangye Yan /
PubMed Abstractγ-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 ...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.
External linksNat Struct Mol Biol / PubMed:37400655
MethodsEM (single particle)
Resolution2.2 - 3.2 Å
Structure data

33671

7y7v

EMDB-33671, PDB-7y7v:
Cryo-EM structure of human apo GABA transporter GAT1 in an inward-open state
Method: EM (single particle) / Resolution: 2.2 Å

33672

7y7w

EMDB-33672, PDB-7y7w:
Cryo-EM structure of human GABA transporter GAT1 bound with GABA in NaCl solution in an inward-occluded state at 2.4 angstrom
Method: EM (single particle) / Resolution: 2.4 Å

33674

7y7y

EMDB-33674, PDB-7y7y:
Cryo-EM structure of human GABA transporter GAT1 bound with nipecotic acid in NaCl solution in an inward-occluded state at 2.4 angstrom
Method: EM (single particle) / Resolution: 2.4 Å

33675

7y7z

EMDB-33675, PDB-7y7z:
Cryo-EM structure of human GABA transporter GAT1 bound with tiagabine in NaCl solution in an inward-open state at 3.2 angstrom
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

ChemComp-NA:
Unknown entry

ChemComp-ID7:
(3R)-piperidine-3-carboxylic acid

ChemComp-TGI:
Tiagabine / medication*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / GABA transporter / GAT1 / Nipecotic acid / Tiagabine / Neurotransmitter / SLC6A1 / SLC6A1.

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