5tf9

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of WNK1 in complex with Mn2+AMPPNP and WNK476

Structural highlights

5tf9 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	, , ,
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

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration and/or stringent hit triaging with high ATP concentration offer conceptually simple methods of identifying allosteric inhibitors. Here we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation anti-hypertensive that requires a stringent safety profile. This strategy yielded several ATP non-competitive WNK1-4 kinase inhibitors, whose optimization enabled co-crystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride co-transporter 1 (NKCC1) in HT29 cells, consistent with the known WNK biology.

Discovery and characterization of allosteric WNK kinase inhibitors.,Yamada K, Zhang JH, Xie X, Reinhardt J, Xie AQ, LaSala D, Kohls D, Yowe D, Burdick D, Yoshisue H, Wakai H, Schmidt I, Gunawan J, Yasoshima K, Yue QK, Kato M, Mogi M, Idamakanti N, Kreder N, Drueckes P, Pandey P, Kawanami T, Huang W, Yagi YI, Deng Z, Park HM ACS Chem Biol. 2016 Oct 7. PMID:27712055^[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, Zhang JH, Xie X, Reinhardt J, Xie AQ, LaSala D, Kohls D, Yowe D, Burdick D, Yoshisue H, Wakai H, Schmidt I, Gunawan J, Yasoshima K, Yue QK, Kato M, Mogi M, Idamakanti N, Kreder N, Drueckes P, Pandey P, Kawanami T, Huang W, Yagi YI, Deng Z, Park HM. Discovery and characterization of allosteric WNK kinase inhibitors. ACS Chem Biol. 2016 Oct 7. PMID:27712055 doi:http://dx.doi.org/10.1021/acschembio.6b00511

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5tf9"

Categories: Homo sapiens | Large Structures | Gunawan J | Xie X

@@ Line 3: / Line 3: @@
 <StructureSection load='5tf9' size='340' side='right'caption='[[5tf9]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tf9]] 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=5TF9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TF9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5tf9]] 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=5TF9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TF9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7AV:{2-[(4-CHLOROPHENYL)METHOXY]PHENYL}{5-[2-(METHYLAMINO)-1,3-THIAZOL-4-YL]-2,3-DIHYDRO-1H-INDOL-1-YL}METHANONE'>7AV</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7AV:{2-[(4-CHLOROPHENYL)METHOXY]PHENYL}{5-[2-(METHYLAMINO)-1,3-THIAZOL-4-YL]-2,3-DIHYDRO-1H-INDOL-1-YL}METHANONE'>7AV</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5tf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tf9 OCA], [https://pdbe.org/5tf9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tf9 RCSB], [https://www.ebi.ac.uk/pdbsum/5tf9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tf9 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5tf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tf9 OCA], [http://pdbe.org/5tf9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tf9 RCSB], [http://www.ebi.ac.uk/pdbsum/5tf9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tf9 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[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.
+[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 ==
-[[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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 29: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Gunawan J]]
-[[Category: Gunawan, J]]
+[[Category: Xie X]]
-[[Category: Xie, X]]
-[[Category: Allosteric]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Serine-threonine-protein kinase]]
-[[Category: Ternary]]
-[[Category: Transferase-transferase inhibitor complex]]

5tf9

From Proteopedia

Current revision

Crystal structure of WNK1 in complex with Mn2+AMPPNP and WNK476

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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