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Cryo-EM structure of human GABA transporter GAT1 bound with GABA in NaCl solution in an inward-occluded state at 2.4 angstrom
Structural highlights
DiseaseSC6A1_HUMAN Myoclonic-astatic epilepsy;Autosomal dominant non-syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry. FunctionSC6A1_HUMAN Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse (PubMed:30132828). The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA (By similarity). The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-) and GABA (By similarity). Can also mediate sodium- and chloride-dependent transport of hypotaurine but to a much lower extent as compared to GABA (By similarity).[UniProtKB:P23978][UniProtKB:P31648][1] Publication Abstract from PubMedgamma-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2-3.2 A. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine. Molecular basis for substrate recognition and transport of human GABA transporter GAT1.,Zhu A, Huang J, Kong F, Tan J, Lei J, Yuan Y, Yan C Nat Struct Mol Biol. 2023 Jul;30(7):1012-1022. doi: 10.1038/s41594-023-00983-z. , Epub 2023 Jul 3. PMID:37400655[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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