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Abstract
The human glycine transporter 1 (GlyTl) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1-3. Inhibition of GlyTl 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 GlyTl in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyTl 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 GlyTl from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyTl inhibitors.
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1 Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
2 Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland
3 European Molecular Biology Laboratory, Hamburg Unit c/o DESY, Hamburg, Germany
4 Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland