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Structural insights into the inhibition of glycine reuptake

Author

Listed:
  • Azadeh Shahsavar

    (Aarhus University
    Hamburg Unit c/o DESY)

  • Peter Stohler

    (Roche Innovation Center)

  • Gleb Bourenkov

    (Hamburg Unit c/o DESY)

  • Iwan Zimmermann

    (University of Zurich
    Linkster Therapeutics AG)

  • Martin Siegrist

    (Roche Innovation Center)

  • Wolfgang Guba

    (Roche Innovation Center)

  • Emmanuel Pinard

    (Roche Innovation Center)

  • Steffen Sinning

    (Aarhus University)

  • Markus A. Seeger

    (University of Zurich)

  • Thomas R. Schneider

    (Hamburg Unit c/o DESY)

  • Roger J. P. Dawson

    (Roche Innovation Center
    Linkster Therapeutics AG)

  • Poul Nissen

    (Aarhus University)

Abstract

The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1–3. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments4. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.

Suggested Citation

  • Azadeh Shahsavar & Peter Stohler & Gleb Bourenkov & Iwan Zimmermann & Martin Siegrist & Wolfgang Guba & Emmanuel Pinard & Steffen Sinning & Markus A. Seeger & Thomas R. Schneider & Roger J. P. Dawson , 2021. "Structural insights into the inhibition of glycine reuptake," Nature, Nature, vol. 591(7851), pages 677-681, March.
    • Handle: RePEc:nat:nature:v:591:y:2021:i:7851:d:10.1038_s41586-021-03274-z
    DOI: 10.1038/s41586-021-03274-z
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    Cited by:

    1. Robert Schönherr & Juliane Boger & J. Mia Lahey-Rudolph & Mareike Harms & Jacqueline Kaiser & Sophie Nachtschatt & Marla Wobbe & Rainer Duden & Peter König & Gleb Bourenkov & Thomas R. Schneider & Lar, 2024. "A streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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