View source for 9ik1


==Cryo-EM structure of the human P2X3 receptor-compound 26a complex==
<StructureSection load='9ik1' size='340' side='right'caption='[[9ik1]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ik1]] is a 3 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=9IK1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9IK1 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]] 2.61&#8491;</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=9ik1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ik1 OCA], [https://pdbe.org/9ik1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ik1 RCSB], [https://www.ebi.ac.uk/pdbsum/9ik1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ik1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/P2RX3_HUMAN P2RX3_HUMAN] Receptor for ATP that acts as a ligand-gated ion channel.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Adelta-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC(50) = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure.

Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.,Kim GR, Kim S, Kim YO, Han X, Nagel J, Kim J, Song DI, Muller CE, Yoon MH, Jin MS, Kim YC J Med Chem. 2024 Aug 22;67(16):14443-14465. doi: 10.1021/acs.jmedchem.4c01214. , Epub 2024 Aug 5. PMID:39102524<ref>PMID:39102524</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ik1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Han X]]
[[Category: Jin MS]]
[[Category: Kim GR]]
[[Category: Kim J]]
[[Category: Kim S]]
[[Category: Kim YC]]
[[Category: Kim YO]]
[[Category: Muller CE]]
[[Category: Nagel J]]
[[Category: Song DI]]
[[Category: Yoon MH]]