Target Information
| Target General Information | Top | |||||
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| Target ID |
T15797
(Former ID: TTDI00213)
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| Target Name |
SET and MYND domain-containing protein 2 (SMYD2)
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| Synonyms |
Nlysine methyltransferase SMYD2; N-lysine methyltransferase SMYD2; Lysine Nmethyltransferase 3C; Lysine N-methyltransferase 3C; KMT3C; Histone methyltransferase SMYD2; HSKMB; HSKM-B
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| Gene Name |
SMYD2
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'. Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.-
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| Sequence |
MRAEGLGGLERFCSPGKGRGLRALQPFQVGDLLFSCPAYAYVLTVNERGNHCEYCFTRKE
GLSKCGRCKQAFYCNVECQKEDWPMHKLECSPMVVFGENWNPSETVRLTARILAKQKIHP ERTPSEKLLAVKEFESHLDKLDNEKKDLIQSDIAALHHFYSKHLGFPDNDSLVVLFAQVN CNGFTIEDEELSHLGSAIFPDVALMNHSCCPNVIVTYKGTLAEVRAVQEIKPGEEVFTSY IDLLYPTEDRNDRLRDSYFFTCECQECTTKDKDKAKVEIRKLSDPPKAEAIRDMVRYARN VIEEFRRAKHYKSPSELLEICELSQEKMSSVFEDSNVYMLHMMYQAMGVCLYMQDWEGAL QYGQKIIKPYSKHYPLYSLNVASMWLKLGRLYMGLEHKAAGEKALKKAIAIMEVAHGKDH PYISEIKQEIESH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T62QAR | |||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | AZ505 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | AZ505 | Drug Info | [4] | |||
| 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 | SMYD2 in complex with small molecule inhibitor compound-2 | PDB:5ARF | ||||
| Method | X-ray diffraction | Resolution | 1.92 Å | Mutation | No | [5] |
| PDB Sequence |
LGGLERFCSP
15 GKGRGLRALQ25 PFQVGDLLFS35 CPAYAYVLTV45 NERGNHCEYC55 FTRKEGLSKC 65 GRCKQAFYCN75 VECQKEDWPM85 HKLECSPMVV95 FGENWNPSET105 VRLTARILAK 115 QKIHPERTPS125 EKLLAVKEFE135 SHLDKLDNEK145 KDLIQSDIAA155 LHHFYSKHLG 165 FPDNDSLVVL175 FAQVNCNGFT185 IEDEELSHLG195 SAIFPDVALM205 NHSCCPNVIV 215 TYKGTLAEVR225 AVQEIKPGEE235 VFTSYIDLLY245 PTEDRNDRLR255 DSYFFTCECQ 265 ECTTKDKDKA275 KVEIRKLSDP285 PKAEAIRDMV295 RYARNVIEEF305 RRAKHYKSPS 315 ELLEICELSQ325 EKMSSVFEDS335 NVYMLHMMYQ345 AMGVCLYMQD355 WEGALQYGQK 365 IIKPYSKHYP375 LYSLNVASMW385 LKLGRLYMGL395 EHKAAGEKAL405 KKAIAIMEVA 415 HGKDHPYISE425 IKQEI
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GLY16
3.297
LYS17
2.882
GLY18
3.932
ARG19
2.058
GLY20
4.258
LEU129
4.875
GLU135
3.341
HIS137
3.020
CYS181
3.590
ASN182
2.978
ALA203
2.634
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: BAY 598 | Ligand Info | |||||
| Structure Description | SMYD2 in complex with SGC probe BAY-598 | PDB:5ARG | ||||
| Method | X-ray diffraction | Resolution | 1.99 Å | Mutation | No | [5] |
| PDB Sequence |
LGGLERFCSP
15 GKGRGLRALQ25 PFQVGDLLFS35 CPAYAYVLTV45 NERGNHCEYC55 FTRKEGLSKC 65 GRCKQAFYCN75 VECQKEDWPM85 HKLECSPMVV95 FGENWNPSET105 VRLTARILAK 115 QKIHPERTPS125 EKLLAVKEFE135 SHLDKLDNEK145 KDLIQSDIAA155 LHHFYSKHLG 165 FPDNDSLVVL175 FAQVNCNGFT185 IEDEELSHLG195 SAIFPDVALM205 NHSCCPNVIV 215 TYKGTLAEVR225 AVQEIKPGEE235 VFTSYIDLLY245 PTEDRNDRLR255 DSYFFTCECQ 265 ECTTKDKDKA275 KVEIRKLSDP285 PKAEAIRDMV295 RYARNVIEEF305 RRAKHYKSPS 315 ELLEICELSQ325 EKMSSVFEDS335 NVYMLHMMYQ345 AMGVCLYMQD355 WEGALQYGQK 365 IIKPYSKHYP375 LYSLNVASMW385 LKLGRLYMGL395 EHKAAGEKAL405 KKAIAIMEVA 415 HGKDHPYISE425 IKQEIE
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GLU104
3.440
THR105
3.358
LEU108
3.492
VAL179
3.194
ASN180
3.792
CYS181
4.205
ASN182
3.517
GLY183
2.607
PHE184
3.423
THR185
2.574
ILE186
4.587
GLU187
3.861
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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 | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.39E-01 | Radiality | 1.42E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.99E+02 | Topological coefficient | 5.38E-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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| 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 | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | p53 pathway | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | PKMTs methylate histone lysines | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Histone Modifications | |||||
| References | Top | |||||
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| REF 1 | 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: 2714). | |||||
| 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 | Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. ACS Med Chem Lett. 2015 Apr 29;6(6):695-700. | |||||
| REF 4 | Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011 Sep 7;19(9):1262-73. | |||||
| REF 5 | Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600. | |||||
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