Target Information
| Target General Information | Top | |||||
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| Target ID |
T52638
(Former ID: TTDI01530)
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| Target Name |
Serine/threonine-protein kinase WNK1 (WNK1)
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| Synonyms |
p65; hWNK1; Protein kinase with no lysine 1; Protein kinase lysine-deficient 1; Kinase deficient protein; KDP; HSN2; Erythrocyte 65 kDa protein
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| Gene Name |
WNK1
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
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. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity).
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MSGGAAEKQSSTPGSLFLSPPAPAPKNGSSSDSSVGEKLGAAAADAVTGRTEEYRRRRHT
MDKDSRGAAATTTTTEHRFFRRSVICDSNATALELPGLPLSLPQPSIPAAVPQSAPPEPH REETVTATATSQVAQQPPAAAAPGEQAVAGPAPSTVPSSTSKDRPVSQPSLVGSKEEPPP ARSGSGGGSAKEPQEERSQQQDDIEELETKAVGMSNDGRFLKFDIEIGRGSFKTVYKGLD TETTVEVAWCELQDRKLTKSERQRFKEEAEMLKGLQHPNIVRFYDSWESTVKGKKCIVLV TELMTSGTLKTYLKRFKVMKIKVLRSWCRQILKGLQFLHTRTPPIIHRDLKCDNIFITGP TGSVKIGDLGLATLKRASFAKSVIGTPEFMAPEMYEEKYDESVDVYAFGMCMLEMATSEY PYSECQNAAQIYRRVTSGVKPASFDKVAIPEVKEIIEGCIRQNKDERYSIKDLLNHAFFQ EETGVRVELAEEDDGEKIAIKLWLRIEDIKKLKGKYKDNEAIEFSFDLERDVPEDVAQEM VESGYVCEGDHKTMAKAIKDRVSLIKRKREQRQLVREEQEKKKQEESSLKQQVEQSSASQ TGIKQLPSASTGIPTASTTSASVSTQVEPEEPEADQHQQLQYQQPSISVLSDGTVDSGQG SSVFTESRVSSQQTVSYGSQHEQAHSTGTVPGHIPSTVQAQSQPHGVYPPSSVAQGQSQG QPSSSSLTGVSSSQPIQHPQQQQGIQQTAPPQQTVQYSLSQTSTSSEATTAQPVSQPQAP QVLPQVSAGKQLPVSQPVPTIQGEPQIPVATQPSVVPVHSGAHFLPVGQPLPTPLLPQYP VSQIPISTPHVSTAQTGFSSLPITMAAGITQPLLTLASSATTAAIPGVSTVVPSQLPTLL QPVTQLPSQVHPQLLQPAVQSMGIPANLGQAAEVPLSSGDVLYQGFPPRLPPQYPGDSNI APSSNVASVCIHSTVLSPPMPTEVLATPGYFPTVVQPYVESNLLVPMGGVGGQVQVSQPG GSLAQAPTTSSQQAVLESTQGVSQVAPAEPVAVAQTQATQPTTLASSVDSAHSDVASGMS DGNENVPSSSGRHEGRTTKRHYRKSVRSRSRHEKTSRPKLRILNVSNKGDRVVECQLETH NRKMVTFKFDLDGDNPEEIATIMVNNDFILAIERESFVDQVREIIEKADEMLSEDVSVEP EGDQGLESLQGKDDYGFSGSQKLEGEFKQPIPASSMPQQIGIPTSSLTQVVHSAGRRFIV SPVPESRLRESKVFPSEITDTVAASTAQSPGMNLSHSASSLSLQQAFSELRRAQMTEGPN TAPPNFSHTGPTFPVVPPFLSSIAGVPTTAAATAPVPATSSPPNDISTSVIQSEVTVPTE EGIAGVATSTGVVTSGGLPIPPVSESPVLSSVVSSITIPAVVSISTTSPSLQVPTSTSEI VVSSTALYPSVTVSATSASAGGSTATPGPKPPAVVSQQAAGSTTVGATLTSVSTTTSFPS TASQLCIQLSSSTSTPTLAETVVVSAHSLDKTSHSSTTGLAFSLSAPSSSSSPGAGVSSY ISQPGGLHPLVIPSVIASTPILPQAAGPTSTPLLPQVPSIPPLVQPVANVPAVQQTLIHS QPQPALLPNQPHTHCPEVDSDTQPKAPGIDDIKTLEEKLRSLFSEHSSSGAQHASVSLET SLVIESTVTPGIPTTAVAPSKLLTSTTSTCLPPTNLPLGTVALPVTPVVTPGQVSTPVST TTSGVKPGTAPSKPPLTKAPVLPVGTELPAGTLPSEQLPPFPGPSLTQSQQPLEDLDAQL RRTLSPEMITVTSAVGPVSMAAPTAITEAGTQPQKGVSQVKEGPVLATSSGAGVFKMGRF QVSVAADGAQKEGKNKSEDAKSVHFESSTSESSVLSSSSPESTLVKPEPNGITIPGISSD VPESAHKTTASEAKSDTGQPTKVGRFQVTTTANKVGRFSVSKTEDKITDTKKEGPVASPP FMDLEQAVLPAVIPKKEKPELSEPSHLNGPSSDPEAAFLSRDVDDGSGSPHSPHQLSSKS LPSQNLSQSLSNSFNSSYMSSDNESDIEDEDLKLELRRLRDKHLKEIQDLQSRQKHEIES LYTKLGKVPPAVIIPPAAPLSGRRRRPTKSKGSKSSRSSSLGNKSPQLSGNLSGQSAASV LHPQQTLHPPGNIPESGQNQLLQPLKPSPSSDNLYSAFTSDGAISVPSLSAPGQGTSSTN TVGATVNSQAAQAQPPAMTSSRKGTFTDDLHKLVDNWARDAMNLSGRRGSKGHMNYEGPG MARKFSAPGQLCISMTSNLGGSAPISAASATSLGHFTKSMCPPQQYGFPATPFGAQWSGT GGPAPQPLGQFQPVGTASLQNFNISNLQKSISNPPGSNLRTT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | 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:5WE8 | ||||
| Method | X-ray diffraction | Resolution | 2.01 Å | Mutation | Yes | [2] |
| PDB Sequence |
TKAVGMSNDG
218 RFLKFDIEIG228 RGSFKTVYKG238 LDTETTVEVA248 WCELQDRKLT258 KSERQRFKEE 268 AEMLKGLQHP278 NIVRFYDSWE288 STCIVLVTEL303 MTSGTLKTYL313 KRFKVMKIKV 323 LRSWCRQILK333 GLQFLHTRTP343 PIIHRDLKCD353 NIFITGPTGS363 VKIGDLGLAT 373 LKRADFAKSV383 IGTPEFMAPE393 MYAAAYDESV403 DVYAFGMCML413 EMATSEYPYS 423 ECQNAAQIYR433 RVTSGVKPAS443 FDKVAIPEVK453 EIIEGCIRQN463 KDERYSIKDL 473 LNHAFFQEET483
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: N-{(3r)-1-[(4-Chlorophenyl)methyl]pyrrolidin-3-Yl}-2-(3-Methoxyphenyl)-N-Methylquinoline-4-Carboxamide | Ligand Info | |||||
| Structure Description | 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:5WE8 | ||||
| Method | X-ray diffraction | Resolution | 2.01 Å | Mutation | Yes | [2] |
| PDB Sequence |
TKAVGMSNDG
218 RFLKFDIEIG228 RGSFKTVYKG238 LDTETTVEVA248 WCELQDRKLT258 KSERQRFKEE 268 AEMLKGLQHP278 NIVRFYDSWE288 STCIVLVTEL303 MTSGTLKTYL313 KRFKVMKIKV 323 LRSWCRQILK333 GLQFLHTRTP343 PIIHRDLKCD353 NIFITGPTGS363 VKIGDLGLAT 373 LKRADFAKSV383 IGTPEFMAPE393 MYAAAYDESV403 DVYAFGMCML413 EMATSEYPYS 423 ECQNAAQIYR433 RVTSGVKPAS443 FDKVAIPEVK453 EIIEGCIRQN463 KDERYSIKDL 473 LNHAFFQEET483
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LEU252
3.398
ARG264
4.468
PHE265
3.392
GLU268
2.776
ALA269
4.150
MET271
3.981
LEU272
3.528
LEU275
4.932
ILE280
4.301
VAL281
2.990
ARG282
4.578
PHE283
3.745
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Similarity Proteins
Human Tissue Distribution
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Chemical Structure based Activity Landscape of Target | Top |
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| References | Top | |||||
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| REF 1 | WNK lysine deficient protein kinase 1 regulates human endometrial stromal cell decidualization, proliferation, and migration in part through mitoge... Biol Reprod. 2017 Sep 1;97(3):400-412. | |||||
| REF 2 | Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models. J Med Chem. 2017 Aug 24;60(16):7099-7107. | |||||
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