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5we8

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(New page: ==Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)== <StructureSection load='5...)
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==Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)==
==Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)==
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<StructureSection load='5we8' size='340' side='right' caption='[[5we8]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
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<StructureSection load='5we8' size='340' side='right'caption='[[5we8]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5we8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WE8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WE8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5we8]] 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=5WE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WE8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A7Y:N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide'>A7Y</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.006&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A7Y:N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide'>A7Y</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5we8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5we8 OCA], [http://pdbe.org/5we8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5we8 RCSB], [http://www.ebi.ac.uk/pdbsum/5we8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5we8 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5we8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5we8 OCA], [https://pdbe.org/5we8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5we8 RCSB], [https://www.ebi.ac.uk/pdbsum/5we8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5we8 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/WNK1_HUMAN WNK1_HUMAN]] Hereditary sensory and autonomic neuropathy type 2;Pseudohypoaldosteronism type 2C. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
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[https://www.uniprot.org/uniprot/WNK1_HUMAN WNK1_HUMAN] Hereditary sensory and autonomic neuropathy type 2;Pseudohypoaldosteronism type 2C. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/WNK1_HUMAN WNK1_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. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L.<ref>PMID:10660600</ref> <ref>PMID:15060842</ref>
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[https://www.uniprot.org/uniprot/WNK1_HUMAN WNK1_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. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L.<ref>PMID:10660600</ref> <ref>PMID:15060842</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.
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Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models.,Yamada K, Levell J, Yoon T, Kohls D, Yowe D, Rigel DF, Imase H, Yuan J, Yasoshima K, DiPetrillo K, Monovich L, Xu L, Zhu M, Kato M, Jain M, Idamakanti N, Taslimi P, Kawanami T, Argikar UA, Kunjathoor V, Xie X, Yagi YI, Iwaki Y, Robinson Z, Park HM J Med Chem. 2017 Aug 3. doi: 10.1021/acs.jmedchem.7b00708. PMID:28771350<ref>PMID:28771350</ref>
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==See Also==
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5we8" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Homo sapiens]]
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[[Category: Kohls, D]]
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[[Category: Large Structures]]
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[[Category: Xie, X]]
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[[Category: Kohls D]]
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[[Category: Inhibitor]]
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[[Category: Xie X]]
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[[Category: Kinase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)

PDB ID 5we8

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