Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism [National Cryo-Electron Microscopy Facility]

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TitleCryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism [National Cryo-Electron Microscopy Facility]
Publication TypeJournal Article
Year of Publication2023
AuthorsNayak SRanjan, Joseph D, Höfner G, Dakua A, Athreya A, Wanner KT, Kanner BI, Penmatsa A
JournalNat Struct Mol Biol
Date Published2023 Jul 03
ISSN1545-9985
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.

URLhttps://www.nature.com/articles/s41594-023-01011-w
DOI10.1038/s41594-023-01011-w
Alternate JournalNat Struct Mol Biol
PubMed ID37400654
PubMed Central ID4303399