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Structural basis of GABA reuptake inhibition

Author

Listed:
  • Zenia Motiwala

    (University of Southern California
    University of Southern California)

  • Nanda Gowtham Aduri

    (University of Southern California
    University of Southern California)

  • Hamidreza Shaye

    (University of Southern California
    University of Southern California
    Stanford University)

  • Gye Won Han

    (University of Southern California
    University of Southern California)

  • Jordy Homing Lam

    (University of Southern California
    University of Southern California)

  • Vsevolod Katritch

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Vadim Cherezov

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Cornelius Gati

    (University of Southern California
    University of Southern California
    University of Southern California)

Abstract

γ-Aminobutyric acid (GABA) transporter 1 (GAT1)1 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 epilepsy2. Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine3, 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 inhibition4. 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.

Suggested Citation

  • Zenia Motiwala & Nanda Gowtham Aduri & Hamidreza Shaye & Gye Won Han & Jordy Homing Lam & Vsevolod Katritch & Vadim Cherezov & Cornelius Gati, 2022. "Structural basis of GABA reuptake inhibition," Nature, Nature, vol. 606(7915), pages 820-826, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04814-x
    DOI: 10.1038/s41586-022-04814-x
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    Cited by:

    1. Huanyu Z. Li & Ashley C. W. Pike & Irina Lotsaris & Gamma Chi & Jesper S. Hansen & Sarah C. Lee & Karin E. J. Rödström & Simon R. Bushell & David Speedman & Adam Evans & Dong Wang & Didi He & Leela Sh, 2024. "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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