6ZPL
Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor, sybody Sb_GlyT1#7 and bound Na and Cl ions.
Summary for 6ZPL
| Entry DOI | 10.2210/pdb6zpl/pdb |
| Related | 6ZBV |
| Descriptor | Sodium- and chloride-dependent glycine transporter 1, Endoglucanase H, Sybody Sb_GlyT1#7, ... (6 entities in total) |
| Functional Keywords | secondary active transport, neurotransmitter-sodium symport, amino acid transport, slc6a9, inward open state, inhibitor bound complex, membrane protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 188483.60 |
| Authors | Shahsavar, A.,Stohler, P.,Bourenkov, G.,Zimmermann, I.,Siegrist, M.,Guba, W.,Pinard, E.,Sinning, S.,Seeger, M.A.,Schneider, T.R.,Dawson, R.J.P.,Nissen, P. (deposition date: 2020-07-08, release date: 2021-03-17, Last modification date: 2024-11-13) |
| Primary citation | Shahsavar, A.,Stohler, P.,Bourenkov, G.,Zimmermann, I.,Siegrist, M.,Guba, W.,Pinard, E.,Sinning, S.,Seeger, M.A.,Schneider, T.R.,Dawson, R.J.P.,Nissen, P. Structural insights into the inhibition of glycine reuptake. Nature, 591:677-681, 2021 Cited by PubMed Abstract: The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine. 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 impairments. 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. PubMed: 33658720DOI: 10.1038/s41586-021-03274-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.945 Å) |
Structure validation
Download full validation report
