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5wdy

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Revision as of 00:17, 16 November 2017

Crystal structure of WNK1 in complex with 1-cyclohexyl-N-({6-fluoro-1-[2-(3-methoxyphenyl)pyridin-4-yl]-1H-indol-3-yl}methyl)methanamine (compound 6)

Structural highlights

5wdy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	WNK1, HSN2, KDP, KIAA0344, PRKWNK1 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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

[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.^[1] ^[2]

Publication Abstract from PubMed

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.

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Moore TM, Garg R, Johnson C, Coptcoat MJ, Ridley AJ, Morris JD. PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J Biol Chem. 2000 Feb 11;275(6):4311-22. PMID:10660600
↑ Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O'Driscoll M, Brais B, Meilleur S, Brinkman RR, Dadivas O, Pape T, Platon C, Radomski C, Risler J, Thompson J, Guerra-Escobio AM, Davar G, Breakefield XO, Pimstone SN, Green R, Pryse-Phillips W, Goldberg YP, Younghusband HB, Hayden MR, Sherrington R, Rouleau GA, Samuels ME. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet. 2004 May;74(5):1064-73. Epub 2004 Apr 1. PMID:15060842 doi:http://dx.doi.org/10.1086/420795
↑ 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. Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models. J Med Chem. 2017 Aug 3. doi: 10.1021/acs.jmedchem.7b00708. PMID:28771350 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00708

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wdy"

@@ Line 3: / Line 3: @@
 <StructureSection load='5wdy' size='340' side='right' caption='[[5wdy]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wdy]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WDY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WDY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wdy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WDY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WDY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A6S:1-cyclohexyl-N-({6-fluoro-1-[2-(3-methoxyphenyl)pyridin-4-yl]-1H-indol-3-yl}methyl)methanamine'>A6S</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">WNK1, HSN2, KDP, KIAA0344, PRKWNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <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>
 <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=5wdy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wdy OCA], [http://pdbe.org/5wdy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wdy RCSB], [http://www.ebi.ac.uk/pdbsum/5wdy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wdy ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Kohls, D]]

5wdy

From Proteopedia

Revision as of 00:17, 16 November 2017

Crystal structure of WNK1 in complex with 1-cyclohexyl-N-({6-fluoro-1-[2-(3-methoxyphenyl)pyridin-4-yl]-1H-indol-3-yl}methyl)methanamine (compound 6)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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