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TitleStructural basis of GABA reuptake inhibition.
Journal, issue, pagesNature, Vol. 606, Issue 7915, Page 820-826, Year 2022
Publish dateJun 8, 2022
AuthorsZenia Motiwala / Nanda Gowtham Aduri / Hamidreza Shaye / Gye Won Han / Jordy Homing Lam / Vsevolod Katritch / Vadim Cherezov / Cornelius Gati /
PubMed Abstractγ-Aminobutyric acid (GABA) transporter 1 (GAT1) regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release ...γ-Aminobutyric acid (GABA) transporter 1 (GAT1) regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy. Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine, with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition. The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins.
External linksNature / PubMed:35676483 / PubMed Central
MethodsEM (single particle)
Resolution3.82 Å
Structure data

25170

7sk2

EMDB-25170, PDB-7sk2:
Human wildtype GABA reuptake transporter 1 in complex with tiagabine, inward-open conformation
Method: EM (single particle) / Resolution: 3.82 Å

Chemicals

ChemComp-TGI:
Tiagabine / medication*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Neurotransmitter transporter

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