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Updated: May 21, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Substrate recognition and allosteric inhibition of human betaine/GABA transporter 1
Jun Zhou1, Jiameng Liu1, Yuchen Jin1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.
Abstract:
The betaine/GABA transporter 1 (BGT1, SLC6A12) regulates neurotransmitter clearance and osmotic balance by transporting GABA and betaine in a sodium- and chloride-dependent manner. BGT1 has become a promising target for epilepsy treatment due to the anticonvulsant effects observed with BGT1 inhibitors. Although BGT1 plays key roles in both renal and neuronal physiology, the molecular basis of its substrate recognition and inhibition remains unclear. Here, we report cryo-EM structures of human BGT1 in the apo form and in complex with GABA, betaine, the substrate-like inhibitor ATPCA, and the selective inhibitor BPDBA all without the use of fiducial markers. These structures capture BGT1 in both occluded and inward-facing conformations, delineating the conformational transitions associated with substrate release. BPDBA binds to an intracellular cavity adjacent to the intracellular gate. This binding mode locks TM1a to transit and inhibits substrate release. Together, our results uncover distinct mechanisms of substrate recognition and allosteric inhibition of hBGT1, offering structural insights for the development of hBGT1-selective modulators.
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