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

DOI: 10.1038/s41594-023-01011-w DOI Help

Authors: Smruti Ranjan Nayak (Indian Institute of Science) , Deepthi Joseph (Indian Institute of Science) , Georg Höfner (Ludwig Maximilians University of Munich) , Archishman Dakua (Indian Institute of Science) , Arunabh Athreya (Indian Institute of Science) , Klaus T. Wanner (Ludwig Maximilians University of Munich) , Baruch I. Kanner (Hebrew University) , Aravind Penmatsa (Indian Institute of Science)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 187

State: Published (Approved)
Published: July 2023
Diamond Proposal Number(s): 31643

Open Access Open Access

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.

Diamond Keywords: Epilepsy

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 05/07/2023 10:13

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)