Target Information
| Target General Information | Top | |||||
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| Target ID |
T73863
(Former ID: TTDI03362)
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| Target Name |
Lysine-specific demethylase 4C (KDM4C)
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| Synonyms |
KIAA0780; Jumonji domain-containing protein 2C; JmjC domain-containing histone demethylation protein 3C; JMJD2C; JHDM3C; Gene amplified in squamous cell carcinoma 1 protein; GASC1; GASC-1 protein
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| Gene Name |
KDM4C
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code.
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| BioChemical Class |
Paired donor oxygen oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.14.11.-
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| Sequence |
MEVAEVESPLNPSCKIMTFRPSMEEFREFNKYLAYMESKGAHRAGLAKVIPPKEWKPRQC
YDDIDNLLIPAPIQQMVTGQSGLFTQYNIQKKAMTVKEFRQLANSGKYCTPRYLDYEDLE RKYWKNLTFVAPIYGADINGSIYDEGVDEWNIARLNTVLDVVEEECGISIEGVNTPYLYF GMWKTTFAWHTEDMDLYSINYLHFGEPKSWYAIPPEHGKRLERLAQGFFPSSSQGCDAFL RHKMTLISPSVLKKYGIPFDKITQEAGEFMITFPYGYHAGFNHGFNCAESTNFATVRWID YGKVAKLCTCRKDMVKISMDIFVRKFQPDRYQLWKQGKDIYTIDHTKPTPASTPEVKAWL QRRRKVRKASRSFQCARSTSKRPKADEEEEVSDEVDGAEVPNPDSVTDDLKVSEKSEAAV KLRNTEASSEEESSASRMQVEQNLSDHIKLSGNSCLSTSVTEDIKTEDDKAYAYRSVPSI SSEADDSIPLSSGYEKPEKSDPSELSWPKSPESCSSVAESNGVLTEGEESDVESHGNGLE PGEIPAVPSGERNSFKVPSIAEGENKTSKSWRHPLSRPPARSPMTLVKQQAPSDEELPEV LSIEEEVEETESWAKPLIHLWQTKSPNFAAEQEYNATVARMKPHCAICTLLMPYHKPDSS NEENDARWETKLDEVVTSEGKTKPLIPEMCFIYSEENIEYSPPNAFLEEDGTSLLISCAK CCVRVHASCYGIPSHEICDGWLCARCKRNAWTAECCLCNLRGGALKQTKNNKWAHVMCAV AVPEVRFTNVPERTQIDVGRIPLQRLKLKCIFCRHRVKRVSGACIQCSYGRCPASFHVTC AHAAGVLMEPDDWPYVVNITCFRHKVNPNVKSKACEKVISVGQTVITKHRNTRYYSCRVM AVTSQTFYEVMFDDGSFSRDTFPEDIVSRDCLKLGPPAEGEVVQVKWPDGKLYGAKYFGS NIAHMYQVEFEDGSQIAMKREDIYTLDEELPKRVKARFSTASDMRFEDTFYGADIIQGER KRQRVLSSRFKNEYVADPVYRTFLKSSFQKKCQKRQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T23FZH | |||||
| 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: 2-(carboxymethylamino)-2-oxoacetic acid | Ligand Info | |||||
| Structure Description | Crystal structure of human KDM4C catalytic domain with OGA | PDB:4XDO | ||||
| Method | X-ray diffraction | Resolution | 1.97 Å | Mutation | No | [3] |
| PDB Sequence |
LNPSCKIMTF
19 RPSMEEFREF29 NKYLAYMESK39 GAHRAGLAKV49 IPPKEWKPRQ59 CYDDIDNLLI 69 PAPIQQMVTG79 QSGLFTQYNI89 QKKAMTVKEF99 RQLANSGKYC109 TPRYLDYEDL 119 ERKYWKNLTF129 VAPIYGADIN139 GSIYDEGVDE149 WNIARLNTVL159 DVVEEECGIS 169 IEGVNTPYLY179 FGMWKTTFAW189 HTEDMDLYSI199 NYLHFGEPKS209 WYAIPPEHGK 219 RLERLAQGFF229 PSSSQGCDAF239 LRHKMTLISP249 SVLKKYGIPF259 DKITQEAGEF 269 MITFPYGYHA279 GFNHGFNCAE289 STNFATVRWI299 DYGKVAKLCT309 CRKDMVKISM 319 DIFVRKFQPD329 RYQLWKQGKD339 IYTIDHTK
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 6-ethyl-2,5-dimethyl-7-oxo-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile | Ligand Info | |||||
| Structure Description | KDM4C bound to pyrazolo-pyrimidine scaffold | PDB:5KR7 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [4] |
| PDB Sequence |
LNPSCKIMTF
19 RPSMEEFREF29 NKYLAYMESK39 GAHRAGLAKV49 IPPKEWKPRQ59 CYDDIDNLLI 69 PAPIQQMVTG79 QSGLFTQYNI89 QKKAMTVKEF99 RQLANSGKYC109 TPRYLDYEDL 119 ERKYWKNLTF129 VAPIYGADIN139 GSIYDEGVDE149 WNIARLNTVL159 DVVEEECGIS 169 IEGVNTPYLY179 FGMWKTTFAW189 HTEDMDLYSI199 NYLHFGEPKS209 WYAIPPEHGK 219 RLERLAQGFF229 PSSSQGCDAF239 LRHKMTLISP249 SVLKKYGIPF259 DKITQEAGEF 269 MITFPYGYHA279 GFNHGFNCAE289 STNFATVRWI299 DYGKVAKLCT309 CRKDMVKISM 319 DIFVRKFQPD329 RYQLWKQGKD339 IYTIDHTKPT349
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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 Similarity Proteins
Human Tissue Distribution
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Inactive histone-lysine N-methyltransferase 2E (KMT2E) | 37.931 (22/58) | 5.00E-03 |
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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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| 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 | ||||||
| References | Top | |||||
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| REF 1 | KDM4 histone demethylase inhibitors for anti-cancer agents: a patent review.Expert Opin Ther Pat. 2015 Feb;25(2):135-44. | |||||
| REF 2 | A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem. 2014 Mar;9(3):566-71. | |||||
| REF 3 | A High-Throughput Mass Spectrometry Assay Coupled with Redox Activity Testing Reduces Artifacts and False Positives in Lysine Demethylase Screening. J Biomol Screen. 2015 Jul;20(6):810-20. | |||||
| REF 4 | Identification of potent, selective KDM5 inhibitors. Bioorg Med Chem Lett. 2016 Sep 1;26(17):4350-4. | |||||
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