Target Information
Target General Information | Top | |||||
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Target ID |
T83174
(Former ID: TTDI01949)
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Target Name |
Protein kinase C iota (PRKCI)
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Synonyms |
nPKC-iota; aPKC-lambda/iota; Protein kinase C iota type; PRKC-lambda/iota; DXS1179E; Atypical protein kinase C-lambda/iota
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Gene Name |
PRKCI
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Target Type |
Literature-reported target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. Involved in early synaptic long term potentiation phase in CA1 hippocampal cells and short term memory formation. Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.11.13
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Sequence |
MPTQRDSSTMSHTVAGGGSGDHSHQVRVKAYYRGDIMITHFEPSISFEGLCNEVRDMCSF
DNEQLFTMKWIDEEGDPCTVSSQLELEEAFRLYELNKDSELLIHVFPCVPERPGMPCPGE DKSIYRRGARRWRKLYCANGHTFQAKRFNRRAHCAICTDRIWGLGRQGYKCINCKLLVHK KCHKLVTIECGRHSLPQEPVMPMDQSSMHSDHAQTVIPYNPSSHESLDQVGEEKEAMNTR ESGKASSSLGLQDFDLLRVIGRGSYAKVLLVRLKKTDRIYAMKVVKKELVNDDEDIDWVQ TEKHVFEQASNHPFLVGLHSCFQTESRLFFVIEYVNGGDLMFHMQRQRKLPEEHARFYSA EISLALNYLHERGIIYRDLKLDNVLLDSEGHIKLTDYGMCKEGLRPGDTTSTFCGTPNYI APEILRGEDYGFSVDWWALGVLMFEMMAGRSPFDIVGSSDNPDQNTEDYLFQVILEKQIR IPRSLSVKAASVLKSFLNKDPKERLGCHPQTGFADIQGHPFFRNVDWDMMEQKQVVPPFK PNISGEFGLDNFDSQFTNEPVQLTPDDDDIVRKIDQSEFEGFEYINPLLMSAEECV Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T71PTC |
Drugs and Modes of Action | Top | |||||
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Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | ICA-1 | Drug Info | Terminated | Solid tumour/cancer | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 2 Inhibitor drugs | + | ||||
1 | ICA-1 | Drug Info | [1] | |||
2 | CRT-0004592 | Drug Info | [3] |
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: Adenosine triphosphate | Ligand Info | |||||
Structure Description | Crystal Structure of PKCiota kinase domain | PDB:3A8W | ||||
Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [4] |
PDB Sequence |
MDPLGLQDFD
246 LLRVIGRGSY256 AKVLLVRLKK266 TDRIYAMKVV276 KKELVNIDWV290 QTEKHVFEQA 300 SNHPFLVGLH310 SCFQTESRLF320 FVIEYVNGGD330 LMFHMQRQRK340 LPEEHARFYS 350 AEISLALNYL360 HERGIIYRDL370 KLDNVLLDSE380 GHIKLTDYGM390 CKEGLRPGDT 400 TSFCGTPNYI411 APEILRGEDY421 GFSVDWWALG431 VLMFEMMAGR441 SPFDTEDYLF 462 QVILEKQIRI472 PRSLSVKAAS482 VLKSFLNKDP492 KERLGCHPQT502 GFADIQGHPF 512 FRNVDWDMME522 QKQVVPPFKP532 NISGEFGLDN542 FDSQFTNEPV552 QLPDDDDIVR 563 KIDQSEFEGF573 EYINPL
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ILE251
3.648
GLY252
3.545
ARG253
3.856
GLY254
3.334
SER255
2.851
TYR256
2.703
ALA257
2.744
VAL259
3.460
ALA272
3.902
LYS274
2.719
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Ligand Name: Bisindolylmaleimide-I | Ligand Info | |||||
Structure Description | Crystal Structure of the Catalytic Domain of Atypical Protein Kinase C-iota | PDB:1ZRZ | ||||
Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | Yes | [5] |
PDB Sequence |
LGLQDFDLLR
249 VIGRGSYAKV259 LLVRLKKTDR269 IYAMKVVKKE279 LVNDDEDIDW289 VQTEKHVFEQ 299 ASNHPFLVGL309 HSCFQTESRL319 FFVIEYVNGG329 DLMFHMQRQR339 KLPEEHARFY 349 SAEISLALNY359 LHERGIIYRD369 LKLDNVLLDS379 EGHIKLTDYG389 MCKEGLRPGD 399 TTSFCGTPNY410 IAPEILRGED420 YGFSVDWWAL430 GVLMFEMMAG440 RSPFDQNTED 459 YLFQVILEKQ469 IRIPRSMSVK479 AASVLKSFLN489 KDPKERLGCL499 PQTGFADIQG 509 HPFFRNVDWD519 MMEQKQVVPP529 FKPVQLPDDD559 DIVRKIDQSE569 FEGFEYINPL 579
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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 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
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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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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Rap1 signaling pathway | hsa04015 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Endocytosis | hsa04144 | Affiliated Target |
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Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
Hippo signaling pathway | hsa04390 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Tight junction | hsa04530 | Affiliated Target |
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Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
Platelet activation | hsa04611 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Insulin signaling pathway | hsa04910 | Affiliated Target |
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Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
Click to Show/Hide the Information of Affiliated Human Pathways |
Degree | 13 | Degree centrality | 1.40E-03 | Betweenness centrality | 2.01E-04 |
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Closeness centrality | 2.41E-01 | Radiality | 1.42E+01 | Clustering coefficient | 3.59E-01 |
Neighborhood connectivity | 4.47E+01 | Topological coefficient | 9.78E-02 | 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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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
References | Top | |||||
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REF 1 | A novel PKC- inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma. Int J Biochem Cell Biol. 2011 May;43(5):784-94. | |||||
REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027592) | |||||
REF 3 | 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: 1490). | |||||
REF 4 | Structures of the PKC-iota kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533-551 in the C-terminal tail and their roles in ATP binding. Acta Crystallogr D Biol Crystallogr. 2010 May;66(Pt 5):577-83. | |||||
REF 5 | Crystal structure of the catalytic domain of human atypical protein kinase C-iota reveals interaction mode of phosphorylation site in turn motif. J Mol Biol. 2005 Sep 30;352(4):918-31. |
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