Target Information

Target General Information

Target ID

T15797 (Former ID: TTDI00213)

Target Name

SET and MYND domain-containing protein 2 (SMYD2)

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

Target Type

Preclinical target

[1]

Disease

[+] 2 Target-related Diseases

Lung cancer [ICD-11: 2C25]

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

UniProt ID

SMYD2_HUMAN

EC Number

EC 2.1.1.-

Sequence

MRAEGLGGLERFCSPGKGRGLRALQPFQVGDLLFSCPAYAYVLTVNERGNHCEYCFTRKE
GLSKCGRCKQAFYCNVECQKEDWPMHKLECSPMVVFGENWNPSETVRLTARILAKQKIHP
ERTPSEKLLAVKEFESHLDKLDNEKKDLIQSDIAALHHFYSKHLGFPDNDSLVVLFAQVN
CNGFTIEDEELSHLGSAIFPDVALMNHSCCPNVIVTYKGTLAEVRAVQEIKPGEEVFTSY
IDLLYPTEDRNDRLRDSYFFTCECQECTTKDKDKAKVEIRKLSDPPKAEAIRDMVRYARN
VIEEFRRAKHYKSPSELLEICELSQEKMSSVFEDSNVYMLHMMYQAMGVCLYMQDWEGAL
QYGQKIIKPYSKHYPLYSLNVASMWLKLGRLYMGLEHKAAGEKALKKAIAIMEVAHGKDH
PYISEIKQEIESH

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3D Structure

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PDB

HIT2.0 ID

T62QAR

Drugs and Modes of Action

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Preclinical Drug(s)

[+] 6 Preclinical Drugs

A-893

Drug Info

Preclinical

Lung cancer

[2]

AZ505

Drug Info

Preclinical

Solid tumour/cancer

[3]

BAY 598

Drug Info

Preclinical

Discovery agent

[3]

EPZ032597

Drug Info

Preclinical

Solid tumour/cancer

[3]

EPZ033294

Drug Info

Preclinical

Solid tumour/cancer

[3]

LLY-507

Drug Info

Preclinical

Solid tumour/cancer

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 6 Inhibitor drugs

A-893

Drug Info

[2]

AZ505

Drug Info

[4]

BAY 598

Drug Info

[5]

EPZ032597

Drug Info

[3]

EPZ033294

Drug Info

[3]

LLY-507

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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

[5]

PDB Sequence

LGGLERFCSP

¹⁵

GKGRGLRALQ

²⁵

PFQVGDLLFS

³⁵

CPAYAYVLTV

⁴⁵

NERGNHCEYC

⁵⁵

FTRKEGLSKC

⁶⁵

GRCKQAFYCN

⁷⁵

VECQKEDWPM

⁸⁵

HKLECSPMVV

⁹⁵

FGENWNPSET

¹⁰⁵

VRLTARILAK

¹¹⁵

QKIHPERTPS

¹²⁵

EKLLAVKEFE

¹³⁵

SHLDKLDNEK

¹⁴⁵

KDLIQSDIAA

¹⁵⁵

LHHFYSKHLG

¹⁶⁵

FPDNDSLVVL

¹⁷⁵

FAQVNCNGFT

¹⁸⁵

IEDEELSHLG

¹⁹⁵

SAIFPDVALM

²⁰⁵

NHSCCPNVIV

²¹⁵

TYKGTLAEVR

²²⁵

AVQEIKPGEE

²³⁵

VFTSYIDLLY

²⁴⁵

PTEDRNDRLR

²⁵⁵

DSYFFTCECQ

²⁶⁵

ECTTKDKDKA

²⁷⁵

KVEIRKLSDP

²⁸⁵

PKAEAIRDMV

²⁹⁵

RYARNVIEEF

³⁰⁵

RRAKHYKSPS

³¹⁵

ELLEICELSQ

³²⁵

EKMSSVFEDS

³³⁵

NVYMLHMMYQ

³⁴⁵

AMGVCLYMQD

³⁵⁵

WEGALQYGQK

³⁶⁵

IIKPYSKHYP

³⁷⁵

LYSLNVASMW

³⁸⁵

LKLGRLYMGL

³⁹⁵

EHKAAGEKAL

⁴⁰⁵

KKAIAIMEVA

⁴¹⁵

HGKDHPYISE

⁴²⁵

IKQEI

Residue

Distance (Å)

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

Residue

Distance (Å)

LEU204

3.281

MET205

3.694

ASN206

2.462

HIS207

2.713

PHE237

4.538

TYR240

3.235

TYR258

2.594

PHE259

4.759

PHE260

3.390

THR261

4.733

CYS262

4.781

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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

[5]

PDB Sequence

LGGLERFCSP

¹⁵

GKGRGLRALQ

²⁵

PFQVGDLLFS

³⁵

CPAYAYVLTV

⁴⁵

NERGNHCEYC

⁵⁵

FTRKEGLSKC

⁶⁵

GRCKQAFYCN

⁷⁵

VECQKEDWPM

⁸⁵

HKLECSPMVV

⁹⁵

FGENWNPSET

¹⁰⁵

VRLTARILAK

¹¹⁵

QKIHPERTPS

¹²⁵

EKLLAVKEFE

¹³⁵

SHLDKLDNEK

¹⁴⁵

KDLIQSDIAA

¹⁵⁵

LHHFYSKHLG

¹⁶⁵

FPDNDSLVVL

¹⁷⁵

FAQVNCNGFT

¹⁸⁵

IEDEELSHLG

¹⁹⁵

SAIFPDVALM

²⁰⁵

NHSCCPNVIV

²¹⁵

TYKGTLAEVR

²²⁵

AVQEIKPGEE

²³⁵

VFTSYIDLLY

²⁴⁵

PTEDRNDRLR

²⁵⁵

DSYFFTCECQ

²⁶⁵

ECTTKDKDKA

²⁷⁵

KVEIRKLSDP

²⁸⁵

PKAEAIRDMV

²⁹⁵

RYARNVIEEF

³⁰⁵

RRAKHYKSPS

³¹⁵

ELLEICELSQ

³²⁵

EKMSSVFEDS

³³⁵

NVYMLHMMYQ

³⁴⁵

AMGVCLYMQD

³⁵⁵

WEGALQYGQK

³⁶⁵

IIKPYSKHYP

³⁷⁵

LYSLNVASMW

³⁸⁵

LKLGRLYMGL

³⁹⁵

EHKAAGEKAL

⁴⁰⁵

KKAIAIMEVA

⁴¹⁵

HGKDHPYISE

⁴²⁵

IKQEIE

Residue

Distance (Å)

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

Residue

Distance (Å)

SER196

3.143

VAL202

3.463

ALA203

3.698

MET205

3.744

TYR217

2.580

THR238

3.704

SER239

3.975

TYR240

3.123

ILE241

4.180

ASP242

4.676

TYR258

3.290

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

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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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Lysine degradation	hsa00310	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	0.00E+00
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

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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PID Pathway

[+] 1 PID Pathways

p53 pathway

Reactome

[+] 1 Reactome Pathways

PKMTs methylate histone lysines

WikiPathways

[+] 1 WikiPathways

Histone Modifications

References

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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

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 3

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286.

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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