ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism

Nayak, SR and Joseph, D and Höfner, G and Dakua, A and Athreya, A and Wanner, KT and Kanner, BI and Penmatsa, A (2023) Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. In: Nature Structural and Molecular Biology, 30 (7). pp. 1023-1032.

nat_str_mol_30-7_1023-1032_2023.pdf - Published Version

Download (11MB) | Preview
Official URL: https://doi.org/10.1038/s41594-023-01011-w


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.

Item Type: Journal Article
Publication: Nature Structural and Molecular Biology
Publisher: Nature Research
Additional Information: The copyright for this article belongs to the Author.
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 24 Jul 2023 12:32
Last Modified: 24 Jul 2023 12:32
URI: https://eprints.iisc.ac.in/id/eprint/82630

Actions (login required)

View Item View Item