9hug: Difference between revisions
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==Inward-open structure of human glycine transporter 2 in substrate-free state== | |||
<StructureSection load='9hug' size='340' side='right'caption='[[9hug]], [[Resolution|resolution]] 2.97Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9hug]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HUG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HUG FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.97Å</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=CLR:CHOLESTEROL'>CLR</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=9hug FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hug OCA], [https://pdbe.org/9hug PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hug RCSB], [https://www.ebi.ac.uk/pdbsum/9hug PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hug ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Chronic neuropathic pain, caused by nerve damage or disease, is increasing in prevalence, but current treatments are ineffective and over-reliant on opioids. The neuronal glycine transporter, GlyT2, regulates inhibitory glycinergic neurotransmission and represents a promising target for new analgesics. However, most GlyT2 inhibitors cause significant side effects, in part due to irreversible inhibition at analgesic doses. Here we develop a reversible inhibitor of GlyT2, RPI-GLYT2-82, and identify its binding site by determining cryo-EM structures of human GlyT2. We capture three fundamental conformational states of GlyT2 in the substrate-free state, and bound to either glycine, RPI-GLYT2-82 or the pseudo-irreversible inhibitor ORG25543. We demonstrate that RPI-GLYT2-82 dissociates from GlyT2 faster than ORG25543, providing analgesia in mouse neuropathic pain models without on-target side-effects or addiction liability. Our data provide a mechanistic understanding of allosteric inhibition of glycine transport, enabling structure-based design of non-opioid analgesics. | |||
A reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects.,Cantwell Chater RP, Peiser-Oliver J, Pati TK, Quinn AS, Lotsaris I, Frangos ZJ, Anderson KE, Tischer AE, Williams-Noonan BJ, Aubrey KR, O'Mara ML, Michaelides M, Mohammadi SA, Cioffi CL, Vandenberg RJ, Shahsavar A Nat Commun. 2026 Feb 16. doi: 10.1038/s41467-026-69616-5. PMID:41698908<ref>PMID:41698908</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9hug" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Anderson KE]] | |||
[[Category: Aubrey KR]] | |||
[[Category: Cantwell Chater RP]] | |||
[[Category: Cioffi CL]] | |||
[[Category: Frangos ZJ]] | |||
[[Category: Lotsaris I]] | |||
[[Category: Michaelides M]] | |||
[[Category: Mohammadi SA]] | |||
[[Category: O Mara ML]] | |||
[[Category: Pati TK]] | |||
[[Category: Peiser-Oliver J]] | |||
[[Category: Quinn AS]] | |||
[[Category: Shahsavar A]] | |||
[[Category: Tischer AE]] | |||
[[Category: Vandenberg RJ]] | |||
[[Category: Williams-Noonan BJ]] | |||
