Target Information
| Target General Information | Top | |||||
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| Target ID |
T63220
(Former ID: TTDI02471)
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| Target Name |
Activated CDC42 kinase 1 (ACK-1)
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| Synonyms |
Tyrosine kinase non-receptor protein 2; ACK1; ACK-1
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| Gene Name |
TNK2
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.2
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| Sequence |
MQPEEGTGWLLELLSEVQLQQYFLRLRDDLNVTRLSHFEYVKNEDLEKIGMGRPGQRRLW
EAVKRRKALCKRKSWMSKVFSGKRLEAEFPPHHSQSTFRKTSPAPGGPAGEGPLQSLTCL IGEKDLRLLEKLGDGSFGVVRRGEWDAPSGKTVSVAVKCLKPDVLSQPEAMDDFIREVNA MHSLDHRNLIRLYGVVLTPPMKMVTELAPLGSLLDRLRKHQGHFLLGTLSRYAVQVAEGM GYLESKRFIHRDLAARNLLLATRDLVKIGDFGLMRALPQNDDHYVMQEHRKVPFAWCAPE SLKTRTFSHASDTWMFGVTLWEMFTYGQEPWIGLNGSQILHKIDKEGERLPRPEDCPQDI YNVMVQCWAHKPEDRPTFVALRDFLLEAQPTDMRALQDFEEPDKLHIQMNDVITVIEGRA ENYWWRGQNTRTLCVGPFPRNVVTSVAGLSAQDISQPLQNSFIHTGHGDSDPRHCWGFPD RIDELYLGNPMDPPDLLSVELSTSRPPQHLGGVKKPTYDPVSEDQDPLSSDFKRLGLRKP GLPRGLWLAKPSARVPGTKASRGSGAEVTLIDFGEEPVVPALRPCAPSLAQLAMDACSLL DETPPQSPTRALPRPLHPTPVVDWDARPLPPPPAYDDVAQDEDDFEICSINSTLVGAGVP AGPSQGQTNYAFVPEQARPPPPLEDNLFLPPQGGGKPPSSAQTAEIFQALQQECMRQLQA PAGSPAPSPSPGGDDKPQVPPRVPIPPRPTRPHVQLSPAPPGEEETSQWPGPASPPRVPP REPLSPQGSRTPSPLVPPGSSPLPPRLSSSPGKTMPTTQSFASDPKYATPQVIQAPGPRA GPCILPIVRDGKKVSSTHYYLLPERPSYLERYQRFLREAQSPEEPTPLPVPLLLPPPSTP APAAPTATVRPMPQAALDPKANFSTNNSNPGARPPPPRATARLPQRGCPGDGPEAGRPAD KIQMAMVHGVTTEECQAALQCHGWSVQRAAQYLKVEQLFGLGLRPRGECHKVLEMFDWNL EQAGCHLLGSWGPAHHKR 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: DEBROMOHYMENIALDISINE | Ligand Info | |||||
| Structure Description | Structure of the ACK1 Kinase Domain bound to Debromohymenialdisine | PDB:1U4D | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [5] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCPEAMDDF174 IREVNAMHSL 184 DHRNLIRLYG194 VVLTPPMKMV204 TELAPLGSLL214 DRLRKHQGHF224 LLGTLSRYAV 234 QVAEGMGYLE244 SKRFIHRDLA254 ARNLLLATRD264 LVKIGDFGLM274 RALPQDHYVM 286 VPFAWCAPES301 LKTRTFSHAS311 DTWMFGVTLW321 EMFTYGQEPW331 IGLNGSQILH 341 KIDKEGERLP351 RPEDCPQDIY361 NVMVQCWAHK371 PEDRPTFVAL381 RDFLLEAQ |
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| Ligand Name: L-betagamma-meATP | Ligand Info | |||||
| Structure Description | Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the CDC42-associated Tyrosine Kinase ACK1 bound to AMP-PCP | PDB:1U54 | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [5] |
| PDB Sequence |
> Chain A
QSLTCLIGEK 124 DLRLLEKLGD134 GVVRRGEWDA147 PSGKTVSVAV157 KCLAMDDFIR176 EVNAMHSLDH 186 RNLIRLYGVV196 LTPPMKMVTE206 LAPLGSLLDR216 LRKHQGHFLL226 GTLSRYAVQV 236 AEGMGYLESK246 RFIHRDLAAR256 NLLLATRDLV266 KIGDFGLMRA276 LPQNDDHVMQ 287 EHRVPFAWCA298 PESLKTRTFS308 HASDTWMFGV318 TLWEMFTYGQ328 EPWIGLNGSQ 338 ILHKIDKEGE348 RLPRPEDCPQ358 DIYNVMVQCW368 AHKPEDRPTF378 VALRDFLLEA 388 QP> Chain B LTCLIGEKDL 126 RLLEKLGDGV139 VRRGEWDAPS149 GKTVSVAVKC159 LEAMDDFIRE177 VNAMHSLDHR 187 NLIRLYGVVL197 TPPMKMVTEL207 APLGSLLDRL217 RKHQGHFLLG227 TLSRYAVQVA 237 EGMGYLESKR247 FIHRDLAARN257 LLLATRDLVK267 IGDFGLMRAL277 PQNDDHYVMQ 287 EHRKVPFAWC297 APESLKTRTF307 SHASDTWMFG317 VTLWEMFTYG327 QEPWIGLNGS 337 QILHKIDKEG347 ERLPRPEDCP357 QDIYNVMVQC367 WAHKPEDRPT377 FVALRDFLLE 387 A
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LEU132[A]
4.060
GLY133[A]
3.535
ASP134[A]
3.654
GLY138[A]
4.753
VAL140[A]
3.697
ALA156[A]
3.422
LYS158[A]
2.720
GLU177[A]
4.785
ILE190[A]
3.847
THR205[A]
3.728
GLU206[A]
2.976
LEU207[A]
3.931
ALA208[A]
3.214
GLY211[A]
4.360
SER212[A]
4.021
ASP252[A]
4.665
ARG256[A]
4.379
ASN257[A]
3.404
LEU259[A]
3.380
GLY269[A]
4.716
ASP270[A]
3.044
LEU132[B]
3.447
GLY133[B]
3.440
ASP134[B]
3.864
GLY138[B]
4.889
VAL140[B]
3.620
ALA156[B]
3.226
LYS158[B]
3.022
ILE190[B]
4.412
THR205[B]
3.934
GLU206[B]
2.867
LEU207[B]
3.633
ALA208[B]
3.206
GLY211[B]
4.505
SER212[B]
3.607
ASP252[B]
4.594
ARG256[B]
3.449
ASN257[B]
3.557
LEU259[B]
3.446
ASP270[B]
2.503
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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).
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
Biological Network Descriptors
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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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| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.79E-05 |
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| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 7.88E+01 | Topological coefficient | 2.94E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TSH Signaling Pathway | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | CDC42 signaling events | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | G13 Signaling Pathway | |||||
| 2 | EGF/EGFR Signaling Pathway | |||||
| 3 | Focal Adhesion | |||||
| References | Top | |||||
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| REF 1 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2246). | |||||
| REF 2 | Kinase modulators for the treatment of cancer. US9416123. | |||||
| REF 3 | Substituted imidazopyr- and imidazotri-azines. US8481733. | |||||
| REF 4 | Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: development of an expedient and divergent synthetic route and prelimin... Bioorg Med Chem Lett. 2007 Apr 15;17(8):2305-9. | |||||
| REF 5 | Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1. J Biol Chem. 2004 Oct 15;279(42):44039-45. | |||||
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