6zbv

Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor and sybody Sb_GlyT1#7

spinqualitylabelsall models 6zbv, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6zbv is a 2 chain structure with sequence from Homo sapiens and Unidentified. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.4Å Ligands: QET Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SC6A9_HUMAN Atypical glycine encephalopathy;Infantile glycine encephalopathy. The disease is caused by variants affecting the gene represented in this entry. Function SC6A9_HUMAN Sodium- and chloride-dependent glycine transporter (PubMed:8183239). Essential for regulating glycine concentrations at inhibitory glycinergic synapses.[UniProtKB:P28571] Sodium- and chloride-dependent glycine transporter. Sodium- and chloride-dependent glycine transporter. Publication Abstract from PubMed The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine(1-3). 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 impairments(4). 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 A 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. Structural insights into the inhibition of glycine reuptake.,Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W, Pinard E, Sinning S, Seeger MA, Schneider TR, Dawson RJP, Nissen P Nature. 2021 Mar;591(7851):677-681. doi: 10.1038/s41586-021-03274-z. Epub 2021 , Mar 3. PMID:33658720 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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