View source for 8edh


==Identification of a class of WNK isoform-specific inhibitors through high-throughput screening==
<StructureSection load='8edh' size='340' side='right'caption='[[8edh]], [[Resolution|resolution]] 3.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8edh]] is a 2 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=8EDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EDH 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]] 3.111&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WGK:ethyl+1-(5,7-dimethoxy-4-methylquinolin-2-yl)piperidine-4-carboxylate'>WGK</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=8edh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8edh OCA], [https://pdbe.org/8edh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8edh RCSB], [https://www.ebi.ac.uk/pdbsum/8edh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8edh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/WNK3_HUMAN WNK3_HUMAN] Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.<ref>PMID:16275911</ref> <ref>PMID:16275913</ref> <ref>PMID:16357011</ref> <ref>PMID:16501604</ref> <ref>PMID:17975670</ref> <ref>PMID:18768590</ref> <ref>PMID:20525693</ref>   Isoform 1, isoform 2, isoform 3 and isoform 4 stimulate the activity of SLC12A1, SLC12A2 and SLC12A3 and inhibit the activity of SLC12A4, SLC12A5, SLC12A6 and SLC12A7. According to PubMed:19470686, isoform 1 inhibits the activity of SLC12A3.<ref>PMID:19470686</ref> <ref>PMID:21613606</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
INTRODUCTION: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative breast cancer and glioblastoma. Here, we searched for and characterized novel WNK kinase inhibitors. METHODS: We used a ~210,000-compound library in a high-throughput screen, re-acquisition and assay, commercial specificity screens and crystallography to identify WNK-isoform-selective inhibitors. RESULTS: We identified five classes of compounds that inhibit the kinase activity of WNK1: quinoline compounds, halo-sulfones, cyclopropane-containing thiazoles, piperazine-containing compounds, and nitrophenol-derived compounds. The compounds are strongly pan-WNK selective, inhibiting all four WNK isoforms. A class of quinoline compounds was identified that further shows selectivity among the WNK isoforms, being more potent toward WNK3 than WNK1. The crystal structure of the quinoline-derived SW120619 bound to the kinase domain of WNK3 reveals active site binding, and comparison to the WNK1 structure reveals the potential origin of isoform specificity. DISCUSSION: The newly discovered classes of compounds may be starting points for generating pharmacological tools and potential drugs treating hypertension and cancer.

Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.,Chlebowicz J, Akella R, Humphreys JM, He H, Kannangara AR, Wei S, Posner B, Goldsmith EJ Drug Des Devel Ther. 2023 Jan 20;17:93-105. doi: 10.2147/DDDT.S389461. , eCollection 2023. PMID:36712947<ref>PMID:36712947</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8edh" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Akella R]]
[[Category: Goldsmith EJ]]