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Structural insights into the inhibition of glycine reuptake

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DOI

  • Azadeh Shahsavar
  • Peter Stohler, Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center
  • ,
  • Gleb Bourenkov, European Molecular Biology Laboratory, Hamburg Unit c/o DESY, Tyskland
  • Iwan Zimmermann, Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland., Linkster Therapeutics, Swaziland
  • Martin Siegrist, Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center
  • ,
  • Wolfgang Guba, Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center
  • ,
  • Emmanuel Pinard, Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center
  • ,
  • Steffen Sinning
  • Markus A. Seeger, Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland., Schweiz
  • Thomas R. Schneider, European Molecular Biology Laboratory, Hamburg Unit c/o DESY
  • ,
  • Roger J. P. Dawson, Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Linkster Therapeutics
  • ,
  • Poul Nissen
The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1,2,3. 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.
OriginalsprogEngelsk
TidsskriftNature
Vol/bind591
Sider (fra-til)677-681
Antal sider5
ISSN1476-4687
DOI
StatusUdgivet - mar. 2021

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