9hue: Difference between revisions

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'''Unreleased structure'''


The entry 9hue is ON HOLD
==Outward-open structure of human glycine transporter 2 bound to allosteric inhibitor ORG25543==
<StructureSection load='9hue' size='340' side='right'caption='[[9hue]], [[Resolution|resolution]] 2.49&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9hue]] 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=9HUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HUE 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]] 2.49&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1EF1:~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-benzamide'>A1EF1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=9hue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hue OCA], [https://pdbe.org/9hue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hue RCSB], [https://www.ebi.ac.uk/pdbsum/9hue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hue 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.


Authors:  
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>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 9hue" 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]]
Retrieved from "https://proteopedia.org/9hue"