View source for 5yve


==Crystal structure of human P2X3 receptor in complex with the AF-219 negative allosteric modulator==
<StructureSection load='5yve' size='340' side='right'caption='[[5yve]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5yve]] 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=5YVE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YVE 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]] 3.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AF9:5-[2,4-bis(azanyl)pyrimidin-5-yl]oxy-2-methoxy-4-propan-2-yl-benzenesulfonamide'>AF9</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=5yve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yve OCA], [https://pdbe.org/5yve PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5yve RCSB], [https://www.ebi.ac.uk/pdbsum/5yve PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5yve 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.
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== Publication Abstract from PubMed ==
Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.

Druggable negative allosteric site of P2X3 receptors.,Wang J, Wang Y, Cui WW, Huang Y, Yang Y, Liu Y, Zhao WS, Cheng XY, Sun WS, Cao P, Zhu MX, Wang R, Hattori M, Yu Y Proc Natl Acad Sci U S A. 2018 May 8;115(19):4939-4944. doi:, 10.1073/pnas.1800907115. Epub 2018 Apr 19. PMID:29674445<ref>PMID:29674445</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5yve" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hattori M]]
[[Category: Wang Y]]