Target Information
| Target General Information | Top | |||||
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| Target ID |
T49102
(Former ID: TTDI03401)
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| Target Name |
NIMA-related kinase 2 (NEK2)
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| Synonyms |
Serine/threonine-protein kinase Nek2; NimA-related protein kinase 2; NimA-like protein kinase 1; Never in mitosis A-related kinase 2; NLK1; NEK2A; HSPK 21
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| Gene Name |
NEK2
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly. NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis. Involved in the regulation of centrosome disjunction. Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MPSRAEDYEVLYTIGTGSYGRCQKIRRKSDGKILVWKELDYGSMTEAEKQMLVSEVNLLR
ELKHPNIVRYYDRIIDRTNTTLYIVMEYCEGGDLASVITKGTKERQYLDEEFVLRVMTQL TLALKECHRRSDGGHTVLHRDLKPANVFLDGKQNVKLGDFGLARILNHDTSFAKTFVGTP YYMSPEQMNRMSYNEKSDIWSLGCLLYELCALMPPFTAFSQKELAGKIREGKFRRIPYRY SDELNEIITRMLNLKDYHRPSVEEILENPLIADLVADEQRRNLERRGRQLGEPEKSQDSS PVLSELKLKEIQLQERERALKAREERLEQKEQELCVRERLAEDKLARAENLLKNYSLLKE RKFLSLASNPELLNLPSSVIKKKVHFSGESKENIMRSENSESQLTSKSKCKDLKKRLHAA QLRAQALSDIEKNYQLKSRQILGMR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T54FKY | |||||
| 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 diphosphate | Ligand Info | |||||
| Structure Description | Human Nek2 kinase ADP-bound | PDB:2W5A | ||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | No | [4] |
| PDB Sequence |
SRAEDYEVLY
12 TIGTGSYGRC22 QKIRRKSDGK32 ILVWKELDYG42 SMTEAEKQML52 VSEVNLLREL 62 KHPNIVRYYD72 RIIDRTNTTL82 YIVMEYCEGG92 DLASVITKGT102 KERQYLDEEF 112 VLRVMTQLTL122 ALKECHRRSL138 HRDLKPANVF148 LDGKQNVKLG158 DFGLARILTS 171 FAKTFVGTPY181 YMSPEQMNRM191 YNEKSDIWSL202 GCLLYELCAL212 MPPFTAFSQK 222 ELAGKIREGK232 FRRIPYRYSD242 ELNEIITRML252 NLKDYHRPSV262 EEILENPLIL 272 EHHHHHH
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| Ligand Name: NU-6102 | Ligand Info | |||||
| Structure Description | Nek2 bound to arylaminopurine 6 | PDB:5M57 | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [5] |
| PDB Sequence |
SRAEDYEVLY
12 TIGTGSYGRC22 QKIRRKSDGK32 ILVWKELDYG42 SMTEAEKQML52 VSEVNLLREL 62 KHPNIVRYYD72 RIIDRTNTTL82 YIVMEYCEGG92 DLASVITKGT102 KERQYLDEEF 112 VLRVMTQLTL122 ALKECHRRSD132 GGHTVLHRDL142 KPANVFLDGK152 QNVKLGDFVG 178 TPYYMSPEQM188 NRMSYNEKSD198 IWSLGCLLYE208 LCALMPPFTA218 FSQKELAGKI 228 REGKFRRIPY238 RYSDELNEII248 TRMLNLKDYH258 RPSVEEILEN268 PLILEHHHHH 278 H
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ILE14
4.285
GLY15
3.799
THR16
4.078
GLY17
3.522
SER18
4.906
TYR19
3.524
CYS22
3.550
VAL35
3.743
LYS37
3.268
VAL68
3.715
MET86
4.132
GLU87
2.841
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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 | 27 | Degree centrality | 2.90E-03 | Betweenness centrality | 1.63E-04 |
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| Closeness centrality | 2.09E-01 | Radiality | 1.37E+01 | Clustering coefficient | 5.61E-01 |
| Neighborhood connectivity | 4.14E+01 | Topological coefficient | 1.75E-01 | Eccentricity | 13 |
| 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 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 | Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1694-7. | |||||
| REF 2 | Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization. J Med Chem. 2010 Nov 11;53(21):7682-98. | |||||
| REF 3 | Irreversible Nek2 kinase inhibitors with cellular activity. J Med Chem. 2011 Jun 23;54(12):4133-46. | |||||
| REF 4 | Insights into the conformational variability and regulation of human Nek2 kinase. J Mol Biol. 2009 Feb 20;386(2):476-85. | |||||
| REF 5 | Structure-guided design of purine-based probes for selective Nek2 inhibition. Oncotarget. 2017 Mar 21;8(12):19089-19124. | |||||
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