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-Structure paper
タイトル | Molecular basis for substrate recognition and transport of human GABA transporter GAT1. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 30, Issue 7, Page 1012-1022, Year 2023 |
掲載日 | 2023年7月3日 |
著者 | Angqi Zhu / Junhao Huang / Fang Kong / Jiaxin Tan / Jianlin Lei / Yafei Yuan / Chuangye Yan / |
PubMed 要旨 | γ-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 ...γ-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 Å. 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. |
リンク | Nat Struct Mol Biol / PubMed:37400655 |
手法 | EM (単粒子) |
解像度 | 2.2 - 3.2 Å |
構造データ | EMDB-33671, PDB-7y7v: EMDB-33672, PDB-7y7w: EMDB-33674, PDB-7y7y: EMDB-33675, PDB-7y7z: |
化合物 | ChemComp-NAG: ChemComp-CL: ChemComp-HOH: ChemComp-ABU: ChemComp-NA: ChemComp-ID7: ChemComp-TGI: |
由来 |
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キーワード | TRANSPORT PROTEIN / GABA transporter / GAT1 / Nipecotic acid / Tiagabine / Neurotransmitter / SLC6A1 / SLC6A1. |