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mitogen-activated protein kinase kinase 4

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Target id: 2065

Nomenclature: mitogen-activated protein kinase kinase 4

Abbreviated Name: MKK4

Family: STE7 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 399 17p12 MAP2K4 mitogen-activated protein kinase kinase 4
Mouse - 397 11 40.53 cM Map2k4 mitogen-activated protein kinase kinase 4
Rat - 397 10 q24 Map2k4 mitogen activated protein kinase kinase 4
Previous and Unofficial Names Click here for help
JNKK1 | MKK4 | PRKMK4 | Sek1 | SERK1 | dual specificity mitogen-activated protein kinase kinase 4
Database Links Click here for help
Alphafold P45985 (Hs), P47809 (Mm)
BRENDA 2.7.12.2
ChEMBL Target CHEMBL2897 (Hs), CHEMBL2201 (Mm)
Ensembl Gene ENSG00000065559 (Hs), ENSMUSG00000033352 (Mm), ENSRNOG00000003834 (Rn)
Entrez Gene 6416 (Hs), 26398 (Mm), 287398 (Rn)
Human Protein Atlas ENSG00000065559 (Hs)
KEGG Enzyme 2.7.12.2
KEGG Gene hsa:6416 (Hs), mmu:26398 (Mm), rno:287398 (Rn)
OMIM 601335 (Hs)
Pharos P45985 (Hs)
RefSeq Nucleotide NM_003010 (Hs), NM_009157 (Mm), NM_001030023 (Rn)
RefSeq Protein NP_003001 (Hs), NP_033183 (Mm), NP_001025194 (Rn)
UniProtKB P45985 (Hs), P47809 (Mm)
Wikipedia MAP2K4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of human non-phosphorylated MKK4 kinase domain complexed with AMP-PNP
PDB Id:  3ALN
Ligand:  AMP-PNP
Resolution:  2.3Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structures of non-phosphorylated MAP2K4
PDB Id:  3VUT
Resolution:  3.5Å
Species:  Human
References:  2
Enzyme Reaction Click here for help
EC Number: 2.7.12.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.0 pIC50 4
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [4]
darizmetinib Small molecule or natural product Hs Inhibition >6.3 pIC50 6
⤷ pIC50 >6.3 (IC50 <5x10-7 M) [6]
Description: Binned value from patent data
MEK inhibitor I Small molecule or natural product Click here for species-specific activity table Hs Inhibition <6.0 pIC50 7
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [7]
compound 11 [PMID: 26431428] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition <5.3 pIC50 5
⤷ pIC50 <5.3 (IC50 >5x10-6 M) [5]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 1,8
Key to terms and symbols Click column headers to sort
Target used in screen: MEK4
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
PLX-4720 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.2 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cellular signalling
Immuno Process:  Immune regulation

References

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1. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

2. Matsumoto T, Kinoshita T, Kirii Y, Tada T, Yamano A. (2012) Crystal and solution structures disclose a putative transient state of mitogen-activated protein kinase kinase 4. Biochem Biophys Res Commun, 425 (2): 195-200. [PMID:22828509]

3. Matsumoto T, Kinoshita T, Kirii Y, Yokota K, Hamada K, Tada T. (2010) Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state. Biochem Biophys Res Commun, 400 (3): 369-73. [PMID:20732303]

4. Pandey A, Volkots DL, Seroogy JM, Rose JW, Yu JC, Lambing JL, Hutchaleelaha A, Hollenbach SJ, Abe K, Giese NA et al.. (2002) Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem, 45 (17): 3772-93. [PMID:12166950]

5. Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N et al.. (1997) Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther, 283 (2): 636-47. [PMID:9353380]

6. Praefke B, Klovekorn P, Selig R, Albrecht W, Laufer S. (2019) Protein kinase mkk4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death. Patent number: WO2019149738A1. Assignee: Heparegenix Gmbh. Priority date: 30/01/2019. Publication date: 08/08/2019.

7. Wityak J, Hobbs FW, Gardner DS, Santella 3rd JB, Petraitis JJ, Sun JH, Favata MF, Daulerio AJ, Horiuchi KY, Copeland RA et al.. (2004) Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. Bioorg Med Chem Lett, 14 (6): 1483-6. [PMID:15006386]

8. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

STE7 family: mitogen-activated protein kinase kinase 4. Last modified on 21/02/2023. Accessed on 19/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2065.