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.
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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 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 |
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