Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism
Year: 2023
Type: article
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.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: Indian Institute of Science, Wellcome Trust, Diamond Light Source, Department of Biotechnology, Ministry of Science and Technology, India, Department of Science and Technology, Ministry of Science and Technology, India, The Wellcome Trust DBT India Alliance, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council
OpenAlex ID: W4382989230