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TitleCryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 7, Page 1023-1032, Year 2023
Publish dateJul 3, 2023
AuthorsSmruti Ranjan Nayak / Deepthi Joseph / Georg Höfner / Archishman Dakua / Arunabh Athreya / Klaus T Wanner / Baruch I Kanner / Aravind Penmatsa /
PubMed AbstractThe inhibitory neurotransmitter γ-aminobutyric acid (GABA) is cleared from the synaptic cleft by the sodium- and chloride-coupled GABA transporter GAT1. Inhibition of GAT1 prolongs the GABAergic ...The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is cleared from the synaptic cleft by the sodium- and chloride-coupled GABA transporter GAT1. Inhibition of GAT1 prolongs the GABAergic signaling at the synapse and is a strategy to treat certain forms of epilepsy. In this study, we present the cryo-electron microscopy structure of Rattus norvegicus GABA transporter 1 (rGAT1) at a resolution of 3.1 Å. The structure elucidation was facilitated by epitope transfer of a fragment-antigen binding (Fab) interaction site from the Drosophila dopamine transporter (dDAT) to rGAT1. The structure reveals rGAT1 in a cytosol-facing conformation, with a linear density in the primary binding site that accommodates a molecule of GABA, a displaced ion density proximal to Na site 1 and a bound chloride ion. A unique insertion in TM10 aids the formation of a compact, closed extracellular gate. Besides yielding mechanistic insights into ion and substrate recognition, our study will enable the rational design of specific antiepileptics.
External linksNat Struct Mol Biol / PubMed:37400654 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

34167

8gnk

EMDB-34167, PDB-8gnk:
CryoEM structure of cytosol-facing, substrate-bound ratGAT1
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

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

ChemComp-CL:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

ChemComp-HOH:
WATER

Source
  • rattus norvegicus (Norway rat)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Neurotransmitter sodium symporter / GABA transporter / solute carrier 6 / secondary active transport

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