Target Information
| Target General Information | Top | |||||
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| Target ID |
T30420
(Former ID: TTDI03543)
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| Target Name |
SET domain containing 8 (KMT5A)
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| Synonyms |
SETD8; SET8; SET07; SET domain-containing protein 8; PRSET7; PR/SET07; PR/SET domain-containing protein 07; PR-Set7; N-lysine methyltransferase KMT5A; Lysine-specific methylase 5A; Lysine N-methyltransferase 5A; Histone-lysine N-methyltransferase KMT5A; H4-K20-HMTase KMT5A
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| Gene Name |
KMT5A
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Liver cancer [ICD-11: 2C12] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration. Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.-
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| Sequence |
MGEGGAAAALVAAAAAAAAAAAAVVAGQRRRRLGRRARCHGPGRAAGGKMSKPCAVEAAA
AAVAATAPGPEMVERRGPGRPRTDGENVFTGQSKIYSYMSPNKCSGMRFPLQEENSVTHH EVKCQGKPLAGIYRKREEKRNAGNAVRSAMKSEEQKIKDARKGPLVPFPNQKSEAAEPPK TPPSSCDSTNAAIAKQALKKPIKGKQAPRKKAQGKTQQNRKLTDFYPVRRSSRKSKAELQ SEERKRIDELIESGKEEGMKIDLIDGKGRGVIATKQFSRGDFVVEYHGDLIEITDAKKRE ALYAQDPSTGCYMYYFQYLSKTYCVDATRETNRLGRLINHSKCGNCQTKLHDIDGVPHLI LIASRDIAAGEELLYDYGDRSKASIEAHPWLKH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | MS2177 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| 2 | UNC0379 | Drug Info | Preclinical | Hepatocellular carcinoma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | MS2177 | Drug Info | [2] | |||
| 2 | UNC0379 | Drug Info | [2] | |||
| 3 | MS453 | Drug Info | [3] | |||
| 4 | nahuoic acid A | Drug Info | [1] | |||
| 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: Ademetionine | Ligand Info | |||||
| Structure Description | Crystal structure of hSETD8 in complex with histone H4K20 norleucine mutant peptide and S-Adenosylmethionine | PDB:5TEG | ||||
| Method | X-ray diffraction | Resolution | 1.30 Å | Mutation | Yes | [4] |
| PDB Sequence |
KSKAELQSEE
202 RKRIDELIES212 GKEEGMKIDL222 IDGKGRGVIA232 TKQFSRGDFV242 VEYHGDLIEI 252 TDAKKREALY262 AQDPSTGCYM272 YYFQYLSKTY282 CVDATRETNR292 LGRLINHSKS 302 GNCQTKLHDI312 DGVPHLILIA322 SRDIAAGEEL332 LYDYGDRSKA342 SIEAHPWLKH 352
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Norleucine | Ligand Info | |||||
| Structure Description | Crystal structure of hSETD8 in complex with histone H4K20 norleucine mutant peptide and S-Adenosylmethionine | PDB:5TEG | ||||
| Method | X-ray diffraction | Resolution | 1.30 Å | Mutation | Yes | [4] |
| PDB Sequence |
KSKAELQSEE
202 RKRIDELIES212 GKEEGMKIDL222 IDGKGRGVIA232 TKQFSRGDFV242 VEYHGDLIEI 252 TDAKKREALY262 AQDPSTGCYM272 YYFQYLSKTY282 CVDATRETNR292 LGRLINHSKS 302 GNCQTKLHDI312 DGVPHLILIA322 SRDIAAGEEL332 LYDYGDRSKA342 SIEAHPWLKH 352
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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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There is no similarity protein (E value < 0.005) for this target
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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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| Lysine degradation | hsa00310 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 2.52E-04 |
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| Closeness centrality | 2.32E-01 | Radiality | 1.41E+01 | Clustering coefficient | 1.94E-01 |
| Neighborhood connectivity | 5.71E+01 | Topological coefficient | 1.39E-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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| 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 | ||||||
| References | Top | |||||
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| REF 1 | Nahuoic acid A produced by a Streptomyces sp. isolated from a marine sediment is a selective SAM-competitive inhibitor of the histone methyltransferase SETD8. Org Lett. 2013 Jan 18;15(2):414-7. | |||||
| REF 2 | Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286. | |||||
| REF 3 | Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. J Med Chem. 2016 Nov 10;59(21):9881-9889. | |||||
| REF 4 | Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8. ACS Med Chem Lett. 2016 Oct 11;7(12):1102-1106. | |||||
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