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Title | Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 30, Issue 7, Page 1023-1032, Year 2023 |
Publish date | Jul 3, 2023 |
Authors | Smruti Ranjan Nayak / Deepthi Joseph / Georg Höfner / Archishman Dakua / Arunabh Athreya / Klaus T Wanner / Baruch I Kanner / Aravind Penmatsa / |
PubMed Abstract | 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 ...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 links | Nat Struct Mol Biol / PubMed:37400654 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.1 Å |
Structure data | EMDB-34167, PDB-8gnk: |
Chemicals | ChemComp-NAG: ChemComp-CL: ChemComp-NA: ChemComp-ABU: ChemComp-CLR: ChemComp-PTY: ChemComp-HOH: |
Source |
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Keywords | MEMBRANE PROTEIN / Neurotransmitter sodium symporter / GABA transporter / solute carrier 6 / secondary active transport |