Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T71367
(Former ID: TTDI00079)
|
|||||
| Target Name |
MEK kinase kinase 4 (MAP4K4)
|
|||||
| Synonyms |
Nckinteracting kinase; Nck-interacting kinase; Mitogenactivated protein kinase kinase kinase kinase 4; Mitogen-activated protein kinase kinase kinase kinase 4; MEKKK 4; MAPK/ERK kinase kinase kinase 4; KIAA0687; HPK/GCKlike kinase HGK; HPK/GCK-like kinase HGK; HGK
Click to Show/Hide
|
|||||
| Gene Name |
MAP4K4
|
|||||
| Target Type |
Patented-recorded target
|
[1] | ||||
| Function |
Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha.
Click to Show/Hide
|
|||||
| BioChemical Class |
Kinase
|
|||||
| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
|
|||||
| Sequence |
MANDSPAKSLVDIDLSSLRDPAGIFELVEVVGNGTYGQVYKGRHVKTGQLAAIKVMDVTE
DEEEEIKLEINMLKKYSHHRNIATYYGAFIKKSPPGHDDQLWLVMEFCGAGSITDLVKNT KGNTLKEDWIAYISREILRGLAHLHIHHVIHRDIKGQNVLLTENAEVKLVDFGVSAQLDR TVGRRNTFIGTPYWMAPEVIACDENPDATYDYRSDLWSCGITAIEMAEGAPPLCDMHPMR ALFLIPRNPPPRLKSKKWSKKFFSFIEGCLVKNYMQRPSTEQLLKHPFIRDQPNERQVRI QLKDHIDRTRKKRGEKDETEYEYSGSEEEEEEVPEQEGEPSSIVNVPGESTLRRDFLRLQ QENKERSEALRRQQLLQEQQLREQEEYKRQLLAERQKRIEQQKEQRRRLEEQQRREREAR RQQEREQRRREQEEKRRLEELERRRKEEEERRRAEEEKRRVEREQEYIRRQLEEEQRHLE VLQQQLLQEQAMLLECRWREMEEHRQAERLQRQLQQEQAYLLSLQHDHRRPHPQHSQQPP PPQQERSKPSFHAPEPKAHYEPADRAREVEDRFRKTNHSSPEAQSKQTGRVLEPPVPSRS ESFSNGNSESVHPALQRPAEPQVPVRTTSRSPVLSRRDSPLQGSGQQNSQAGQRNSTSIE PRLLWERVEKLVPRPGSGSSSGSSNSGSQPGSHPGSQSGSGERFRVRSSSKSEGSPSQRL ENAVKKPEDKKEVFRPLKPADLTALAKELRAVEDVRPPHKVTDYSSSSEESGTTDEEDDD VEQEGADESTSGPEDTRAASSLNLSNGETESVKTMIVHDDVESEPAMTPSKEGTLIVRQT QSASSTLQKHKSSSSFTPFIDPRLLQISPSSGTTVTSVVGFSCDGMRPEAIRQDPTRKGS VVNVNPTNTRPQSDTPEIRKYKKRFNSEILCAALWGVNLLVGTESGLMLLDRSGQGKVYP LINRRRFQQMDVLEGLNVLVTISGKKDKLRVYYLSWLRNKILHNDPEVEKKQGWTTVGDL EGCVHYKVVKYERIKFLVIALKSSVEVYAWAPKPYHKFMAFKSFGELVHKPLLVDLTVEE GQRLKVIYGSCAGFHAVDVDSGSVYDIYLPTHIQCSIKPHAIIILPNTDGMELLVCYEDE GVYVNTYGRITKDVVLQWGEMPTSVAYIRSNQTMGWGEKAIEIRSVETGHLDGVFMHKRA QRLKFLCERNDKVFFASVRSGGSSQVYFMTLGRTSLLSW Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) Bound to AMPPNP | PDB:4U40 | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [4] |
| PDB Sequence |
SLRDPAGIFE
26 LVEVVGNGTY36 GQVYKGRHVK46 TGQLAAIKVM56 DVTEDEEEEI66 KLEINMLKKY 76 SHHRNIATYY86 GAFIKKSPPG96 HDDQLWLVME106 FCGAGSITDL116 VKNTKGNTLK 126 EDWIAYISRE136 ILRGLAHLHI146 HHVIHRDIKG156 QNVLLTENAE166 VKLVDFGVSA 176 QLDRTVGRRN186 TFIGTPYWMA196 PEVIACDENP206 DATYDYRSDL216 WSCGITAIEM 226 AEGAPPLCDM236 HPMRALFLIP246 RNPPPRLKSK256 KWSKKFFSFI266 EGCLVKNYMQ 276 RPSTEQLLKH286 PFIRDQPNER296 QVRIQLKDHI306 DRTRK
|
|||||
|
|
VAL31
4.280
GLY32
3.623
ASN33
3.560
GLY34
4.502
THR35
3.069
TYR36
4.697
VAL39
3.491
ALA52
3.153
LYS54
2.735
ALA83
4.748
MET105
3.464
GLU106
2.900
|
|||||
| Ligand Name: 6-(3-Chlorophenyl)quinazolin-4-Amine | Ligand Info | |||||
| Structure Description | MAP4K4 in complex with inhibitor (compound 22), 6-(3-CHLOROPHENYL)QUINAZOLIN-4-AMINE | PDB:4OBO | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [3] |
| PDB Sequence |
SSLRDPAGIF
25 ELVEVVGNGT35 YGQVYKGRHV45 KTGQLAAIKV55 MDVTEIKLEI70 NMLKKYSHHR 80 NIATYYGAFI90 KKSDDQLWLV104 MEFCGAGSIT114 DLVKNTKGNT124 LKEDWIAYIS 134 REILRGLAHL144 HIHHVIHRDI154 KGQNVLLTEN164 AEVKLVDFGR185 NTFIGTPYWM 195 APEVIACDEN205 PDATYDYRSD215 LWSCGITAIE225 MAEGAPPLCD235 MHPMRALFLI 245 PRNPPPRLKS255 KKWSKKFFSF265 IEGCLVKNYM275 QRPSTEQLLK285 HPFIRDQPNE 295 RQVRIQLKDH305 IDRTR
|
|||||
|
|
||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
|---|---|
|
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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
|
|
|
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.
|
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
|---|---|---|---|
| MAPK signaling pathway | hsa04010 | Affiliated Target |
|
| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
|---|---|---|---|---|---|
| Closeness centrality | 1.91E-01 | Radiality | 1.32E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 4.30E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
|---|---|
| Drug Property Profile of Target | Top | |
|---|---|---|
| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
|
||
| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
|
||
| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
|
||
| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-regulating microRNAs | ||||||
| Target Affiliated Biological Pathways | Top | |||||
|---|---|---|---|---|---|---|
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | FSH Signaling Pathway | |||||
| 2 | TCR Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Apoptosis signaling pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | EPHB forward signaling | |||||
| 2 | TNF receptor signaling pathway | |||||
| 3 | Ceramide signaling pathway | |||||
| 4 | Direct p53 effectors | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Oxidative Stress Induced Senescence | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Insulin Signaling | |||||
| 2 | MAPK Signaling Pathway | |||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1051-5. | |||||
| REF 2 | Aminoquinazoline and pyridopyrimidine derivatives. US9592235. | |||||
| REF 3 | Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization. J Med Chem. 2014 Apr 24;57(8):3484-93. | |||||
| REF 4 | Structural Plasticity and Kinase Activation in a Cohort of MAP4K4 Structures | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.