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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.== | |||
<StructureSection load='6zpl' size='340' side='right'caption='[[6zpl]], [[Resolution|resolution]] 3.94Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6zpl]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Acetivibrio_thermocellus_ATCC_27405 Acetivibrio thermocellus ATCC 27405], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZPL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZPL FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.945Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=QET:[5-fluoranyl-6-(oxan-4-yloxy)-1,3-dihydroisoindol-2-yl]-[5-methylsulfonyl-2-[2,2,3,3,3-pentakis(fluoranyl)propoxy]phenyl]methanone'>QET</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zpl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zpl OCA], [https://pdbe.org/6zpl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zpl RCSB], [https://www.ebi.ac.uk/pdbsum/6zpl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zpl ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GUNH_ACET2 GUNH_ACET2] This enzyme catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin and cereal beta-D-glucans. | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:33658720</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6zpl" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Acetivibrio thermocellus ATCC 27405]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Unidentified]] | |||
[[Category: Bourenkov G]] | |||
[[Category: Dawson RJP]] | |||
[[Category: Guba W]] | |||
[[Category: Nissen P]] | |||
[[Category: Pinard E]] | |||
[[Category: Schneider TR]] | |||
[[Category: Seeger MA]] | |||
[[Category: Shahsavar A]] | |||
[[Category: Siegrist M]] | |||
[[Category: Sinning S]] | |||
[[Category: Stohler P]] | |||
[[Category: Zimmermann I]] | |||
Latest revision as of 14:55, 1 February 2024
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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