Target Information

Target General Information

Top

Target ID

T35792

Target Name

Histone-lysine N-methyltransferase SMYD3 (SMYD3)

Synonyms

SET and MYND domain-containing protein 3; Zinc finger MYND domain-containing protein 1

Click to Show/Hide

Gene Name

SMYD3

Target Type

Preclinical target

[1]

Disease

[+] 2 Target-related Diseases

Colon cancer [ICD-11: 2B90]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Histone methyltransferase. Specifically methylates 'Lys-4' of histone H3, inducing di- and tri-methylation, but not monomethylation . Also methylates 'Lys-5' of histone H4. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.

Click to Show/Hide

UniProt ID

SMYD3_HUMAN

EC Number

EC 2.1.1.354

Sequence

MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSRGVVCDRCLLGKEKLM
RCSQCRVAKYCSAKCQKKAWPDHKRECKCLKSCKPRYPPDSVRLLGRVVFKLMDGAPSES
EKLYSFYDLESNINKLTEDKKEGLRQLVMTFQHFMREEIQDASQLPPAFDLFEAFAKVIC
NSFTICNAEMQEVGVGLYPSISLLNHSCDPNCSIVFNGPHLLLRAVRDIEVGEELTICYL
DMLMTSEERRKQLRDQYCFECDCFRCQTQDKDADMLTGDEQVWKEVQESLKKIEELKAHW
KWEQVLAMCQAIISSNSERLPDINIYQLKVLDCAMDACINLGLLEEALFYGTRTMEPYRI
FFPGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIMRVTHGREHSLIEDLILLLEE
CDANIRAS

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

Top

Preclinical Drug(s)

[+] 4 Preclinical Drugs

EPZ028862

Drug Info

Preclinical

Solid tumour/cancer

[1]

EPZ031686

Drug Info

Preclinical

Solid tumour/cancer

[2]

EPZ0330456

Drug Info

Preclinical

Colon cancer

[1]

GSK2807

Drug Info

Preclinical

Solid tumour/cancer

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 4 Inhibitor drugs

EPZ028862

Drug Info

[1]

EPZ031686

Drug Info

[2]

EPZ0330456

Drug Info

[1]

GSK2807

Drug Info

[3]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

Top

Ligand Name: Ademetionine

Ligand Info

Structure Description

Co-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors

PDB:6P7Z

Method

X-ray diffraction

Resolution

1.19 Å

Mutation

[4]

PDB Sequence

PLKVEKFATA

¹²

NRGNGLRAVT

²²

PLRPGELLFR

³²

SDPLAYTVCK

⁴²

GSRGVVCDRC

⁵²

LLGKEKLMRC

⁶²

SQCRVAKYCS

⁷²

AKCQKKAWPD

⁸²

HKRECKCLKS

⁹²

CPRYPPDSVR

¹⁰³

LLGRVVFKLM

¹¹³

DGAPSESEKL

¹²³

YSFYDLESNI

¹³³

NKLTEDKKEG

¹⁴³

LRQLVMTFQH

¹⁵³

FMREEIQDAS

¹⁶³

QLPPAFDLFE

¹⁷³

AFAKVICNSF

¹⁸³

TICNAEMQEV

¹⁹³

GVGLYPSISL

²⁰³

LNHSCDPNCS

²¹³

IVFNGPHLLL

²²³

RAVRDIEVGE

²³³

ELTICYLDML

²⁴³

MTSEERRKQL

²⁵³

RDQYCFECDC

²⁶³

FRCQTQDKDA

²⁷³

DMLTGDEQVW

²⁸³

KEVQESLKKI

²⁹³

EELKAHWKWE

³⁰³

QVLAMCQAII

³¹³

SSNSERLPDI

³²³

NIYQLKVLDC

³³³

AMDACINLGL

³⁴³

LEEALFYGTR

³⁵³

TMEPYRIFFP

³⁶³

GSHPVRGVQV

³⁷³

MKVGKLQLHQ

³⁸³

GMFPQAMKNL

³⁹³

RLAFDIMRVT

⁴⁰³

HGREHSLIED

⁴¹³

LILLLEECDA

⁴²³

NIRAS

Residue

Distance (Å)

ASN13

4.419

ARG14

2.652

GLY15

3.715

ASN16

2.798

TYR124

2.647

ASP128

4.871

LEU129

4.743

GLU130

3.654

ASN132

2.897

CYS180

3.735

ASN181

3.259

Residue

Distance (Å)

SER202

2.982

LEU203

3.687

LEU204

3.549

ASN205

2.877

HIS206

2.927

TYR239

3.284

TYR257

2.651

CYS258

4.725

PHE259

3.318

GLU260

4.722

CYS261

4.944

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: GSK2807

Ligand Info

Structure Description

Co-crystal structure of human SMYD3 with an aza-SAH compound

PDB:5HI7

Method

X-ray diffraction

Resolution

2.15 Å

Mutation

[3]

PDB Sequence

PLKVEKFATA

¹²

NRGNGLRAVT

²²

PLRPGELLFR

³²

SDPLAYTVCK

⁴²

GSRGVVCDRC

⁵²

LLGKEKLMRC

⁶²

SQCRVAKYCS

⁷²

AKCQKKAWPD

⁸²

HKRECKCLKS

⁹²

CKPRYPPDSV

¹⁰²

RLLGRVVFKL

¹¹²

MDGAPSESEK

¹²²

LYSFYDLESN

¹³²

INKLTEDKKE

¹⁴²

GLRQLVMTFQ

¹⁵²

HFMREEIQDA

¹⁶²

SQLPPAFDLF

¹⁷²

EAFAKVICNS

¹⁸²

FTICNAEMQE

¹⁹²

VGVGLYPSIS

²⁰²

LLNHSCDPNC

²¹²

SIVFNGPHLL

²²²

LRAVRDIEVG

²³²

EELTICYLDM

²⁴²

LMTSEERRKQ

²⁵²

LRDQYCFECD

²⁶²

CFRCQTQDKD

²⁷²

ADMLTGDEQV

²⁸²

WKEVQESLKK

²⁹²

IEELKAHWKW

³⁰²

EQVLAMCQAI

³¹²

ISSNSERLPD

³²²

INIYQLKVLD

³³²

CAMDACINLG

³⁴²

LLEEALFYGT

³⁵²

RTMEPYRIFF

³⁶²

PGSHPVRGVQ

³⁷²

VMKVGKLQLH

³⁸²

QGMFPQAMKN

³⁹²

LRLAFDIMRV

⁴⁰²

THGREHSLIE

⁴¹²

DLILLLEECD

⁴²²

ANIRAS

Residue

Distance (Å)

ARG14

2.879

GLY15

3.414

ASN16

2.126

GLY17

4.714

TYR124

2.265

ASP128

4.788

LEU129

4.149

GLU130

2.826

ASN132

1.845

LYS135

4.076

CYS180

3.171

ASN181

2.776

SER182

3.599

PHE183

3.288

Residue

Distance (Å)

SER202

3.046

LEU203

3.442

LEU204

3.815

ASN205

2.884

HIS206

2.080

SER207

4.655

ILE237

4.079

TYR239

3.376

TYR257

2.625

CYS258

4.458

PHE259

3.139

GLU260

4.290

CYS261

4.258

ASP262

4.812

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

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

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	3	Degree centrality	3.22E-04	Betweenness centrality	2.02E-04
Closeness centrality	2.32E-01	Radiality	1.41E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	7.90E+01	Topological coefficient	3.68E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

References

Top

REF 1

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

REF 2

Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. Expert Opin Ther Targets. 2017 Feb;21(2):145-157.

REF 3

Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets. Structure. 2016 May 3;24(5):774-781.

REF 4

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors. ACS Med Chem Lett. 2019 Dec 27;11(2):133-140.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.

Prof. Feng ZHU

Prof. Yuzong CHEN