Target Information
Target General Information | Top | |||||
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Target ID |
T65501
(Former ID: TTDR01100)
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Target Name |
DNA [cytosine-5]-methyltransferase 3B (DNMT3B)
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Synonyms |
M.HsaIIIB; Dnmt3b; DNA methyltransferase HsaIIIB; DNA methyltransferase 3B; DNA MTase HsaIIIB; DNA (cytosine-5)-methyltransferase 3B
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Gene Name |
DNMT3B
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing. In association with DNMT1 and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Function as transcriptional corepressor by associating with ZHX1. Required for DUX4 silencing in somatic cells. Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
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BioChemical Class |
Methyltransferase
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UniProt ID | ||||||
EC Number |
EC 2.1.1.37
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Sequence |
MKGDTRHLNGEEDAGGREDSILVNGACSDQSSDSPPILEAIRTPEIRGRRSSSRLSKREV
SSLLSYTQDLTGDGDGEDGDGSDTPVMPKLFRETRTRSESPAVRTRNNNSVSSRERHRPS PRSTRGRQGRNHVDESPVEFPATRSLRRRATASAGTPWPSPPSSYLTIDLTDDTEDTHGT PQSSSTPYARLAQDSQQGGMESPQVEADSGDGDSSEYQDGKEFGIGDLVWGKIKGFSWWP AMVVSWKATSKRQAMSGMRWVQWFGDGKFSEVSADKLVALGLFSQHFNLATFNKLVSYRK AMYHALEKARVRAGKTFPSSPGDSLEDQLKPMLEWAHGGFKPTGIEGLKPNNTQPVVNKS KVRRAGSRKLESRKYENKTRRRTADDSATSDYCPAPKRLKTNCYNNGKDRGDEDQSREQM ASDVANNKSSLEDGCLSCGRKNPVSFHPLFEGGLCQTCRDRFLELFYMYDDDGYQSYCTV CCEGRELLLCSNTSCCRCFCVECLEVLVGTGTAAEAKLQEPWSCYMCLPQRCHGVLRRRK DWNVRLQAFFTSDTGLEYEAPKLYPAIPAARRRPIRVLSLFDGIATGYLVLKELGIKVGK YVASEVCEESIAVGTVKHEGNIKYVNDVRNITKKNIEEWGPFDLVIGGSPCNDLSNVNPA RKGLYEGTGRLFFEFYHLLNYSRPKEGDDRPFFWMFENVVAMKVGDKRDISRFLECNPVM IDAIKVSAAHRARYFWGNLPGMNRPVIASKNDKLELQDCLEYNRIAKLKKVQTITTKSNS IKQGKNQLFPVVMNGKEDVLWCTELERIFGFPVHYTDVSNMGRGARQKLLGRSWSVPVIR HLFAPLKDYFACE Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T33BF9 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | Curcumin | Drug Info | Phase 3 | Solid tumour/cancer | [2], [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 22 Inhibitor drugs | + | ||||
1 | Curcumin | Drug Info | [1] | |||
2 | PMID27376512-Compound-MTC-422 | Drug Info | [4] | |||
3 | PMID27376512-Compound-MTC-423 | Drug Info | [4] | |||
4 | PMID27376512-Compound-MTC-424 | Drug Info | [4] | |||
5 | PMID27376512-Compound-MTC-427 | Drug Info | [4] | |||
6 | (L-)-S-adenosyl-L-homocysteine | Drug Info | [1], [5] | |||
7 | NSC-106084 | Drug Info | [1] | |||
8 | NSC-137546 | Drug Info | [1] | |||
9 | NSC-138419 | Drug Info | [1] | |||
10 | NSC-154957 | Drug Info | [1] | |||
11 | NSC-158324 | Drug Info | [1] | |||
12 | NSC-319745 | Drug Info | [1] | |||
13 | NSC-345763 | Drug Info | [1] | |||
14 | NSC-348926 | Drug Info | [1] | |||
15 | NSC-401077 | Drug Info | [1] | |||
16 | NSC-54162 | Drug Info | [1] | |||
17 | NSC-56071 | Drug Info | [1] | |||
18 | NSC-57893 | Drug Info | [1] | |||
19 | NSC-622444 | Drug Info | [1] | |||
20 | NSC-622445 | Drug Info | [1] | |||
21 | NSC-623548 | Drug Info | [1] | |||
22 | S-tubercidinylhomocysteine | Drug Info | [6] |
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: Ethambutol | Ligand Info | |||||
Structure Description | Human DNMT3B PWWP domain in complex with ethambutol | PDB:5NR3 | ||||
Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [7] |
PDB Sequence |
EYQDGKEFGI
225 GDLVWGKIKG235 FSWWPAMVVS245 WKATSKRQAM255 SGMRWVQWFG265 DGKFSEVSAD 275 KLVALGLFSQ285 HFNLATFNKL295 VSYRKAMYHA305 LEKARVRAGK315 TFPDSLEDQL 329 KPMLEWAHGG339 FKPTGIEGLK349 P
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Ligand Name: Triisopropanolamine | Ligand Info | |||||
Structure Description | Human DNMT3B PWWP domain in complex with triisopropanolamine | PDB:6R3E | ||||
Method | X-ray diffraction | Resolution | 2.27 Å | Mutation | No | [8] |
PDB Sequence |
SEYQDGKEFG
224 IGDLVWGKIK234 GFSWWPAMVV244 SWKATSKRQA254 MSGMRWVQWF264 GDGKFSEVSA 274 DKLVALGLFS284 QHFNLATFNK294 LVSYRKAMYH304 ALEKARVRAG314 KTFPSSLEDQ 328 LKPMLEWAHG338 GFKPTGIEGL348 KPN
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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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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Transcriptional regulator ATRX (ATRX) | 28.671 (41/143) | 2.84E-07 |
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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Cysteine and methionine metabolism | hsa00270 | Affiliated Target |
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Class: Metabolism => Amino acid metabolism | Pathway Hierarchy |
Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 1.10E-04 |
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Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.17E-01 |
Neighborhood connectivity | 4.58E+01 | Topological coefficient | 1.75E-01 | Eccentricity | 11 |
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 |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
1 | Cysteine and methionine metabolism | |||||
2 | Metabolic pathways | |||||
3 | MicroRNAs in cancer | |||||
Reactome | [+] 3 Reactome Pathways | + | ||||
1 | PRC2 methylates histones and DNA | |||||
2 | NoRC negatively regulates rRNA expression | |||||
3 | DNA methylation | |||||
WikiPathways | [+] 5 WikiPathways | + | ||||
1 | Mesodermal Commitment Pathway | |||||
2 | Endoderm Differentiation | |||||
3 | Trans-sulfuration and one carbon metabolism | |||||
4 | One Carbon Metabolism | |||||
5 | miR-targeted genes in lymphocytes - TarBase |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation. Bioorg Med Chem. 2010 Jan 15;18(2):822-9. | |||||
REF 2 | 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. (Ligand id: 7000). | |||||
REF 3 | Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68. | |||||
REF 4 | DNA methyltransferase inhibitors: an updated patent review (2012-2015).Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. | |||||
REF 5 | Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors. Bioorg Med Chem Lett. 2009 May 15;19(10):2742-6. | |||||
REF 6 | SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes. Bioorg Med Chem Lett. 2009 May 15;19(10):2747-51. | |||||
REF 7 | Targeting PWWP domain of DNA methyltransferase 3B for epigenetic cancer therapy: Identification and structural characterization of new potential protein-protein interaction inhibitors | |||||
REF 8 | Targeting PWWP domain of DNMT3B for epigenetic cancer therapy: identification and structural characterization of potential protein-protein interaction inhibitors |
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