6zbv | pdb_00006zbv

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

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]^[1] Sodium- and chloride-dependent glycine transporter.^[2] Sodium- and chloride-dependent glycine transporter.^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W, Pinard E, Sinning S, Seeger MA, Schneider TR, Dawson RJP, Nissen P. Structural insights into the inhibition of glycine reuptake. Nature. 2021 Mar;591(7851):677-681. PMID:33658720 doi:10.1038/s41586-021-03274-z

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OCA

[1] Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239

[2] Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239

[3] Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239

[4] Shahsavar A, Stohler P, Bourenkov G, Zimmermann I, Siegrist M, Guba W, Pinard E, Sinning S, Seeger MA, Schneider TR, Dawson RJP, Nissen P. Structural insights into the inhibition of glycine reuptake. Nature. 2021 Mar;591(7851):677-681. PMID:33658720 doi:10.1038/s41586-021-03274-z

[1]

[2]

[3]

[4]

6zbv | pdb_00006zbv

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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