Structural insights into the inhibition of glycine reuptake

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 () and Poul Nissen ()
Additional contact information
Azadeh Shahsavar: Aarhus University
Peter Stohler: Roche Innovation Center
Gleb Bourenkov: Hamburg Unit c/o DESY
Iwan Zimmermann: University of Zurich
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
Poul Nissen: Aarhus University

Nature, 2021, vol. 591, issue 7851, 677-681

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03274-z

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