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Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor, sybody Sb_GlyT1#7 and bound Na and Cl ions.Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor, sybody Sb_GlyT1#7 and bound Na and Cl ions.
Structural highlights
FunctionGUNH_ACET2 This enzyme catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin and cereal beta-D-glucans. Publication Abstract from PubMedThe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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