Target Information

Target General Information

Target ID

T53251 (Former ID: TTDI03186)

Target Name

Histone-lysine N-methyltransferase EHMT2 (EHMT2)

Synonyms

Protein G9a; NG36; Lysine N-methyltransferase 1C; KMT1C; Histone H3-K9 methyltransferase 3; HLA-B-associated transcript 8; H3-K9-HMTase 3; G9A; Euchromatic histone-lysine N-methyltransferase 2; C6orf30; BAT8

Click to Show/Hide

Gene Name

EHMT2

Target Type

Preclinical target

[1]

Disease

[+] 3 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Postoperative inflammation [ICD-11: 1A00-CA43]

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

Function

H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself. Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin.

Click to Show/Hide

BioChemical Class

Methyltransferase

UniProt ID

EHMT2_HUMAN

EC Number

EC 2.1.1.-

Sequence

MAAAAGAAAAAAAEGEAPAEMGALLLEKETRGATERVHGSLGDTPRSEETLPKATPDSLE
PAGPSSPASVTVTVGDEGADTPVGATPLIGDESENLEGDGDLRGGRILLGHATKSFPSSP
SKGGSCPSRAKMSMTGAGKSPPSVQSLAMRLLSMPGAQGAAAAGSEPPPATTSPEGQPKV
HRARKTMSKPGNGQPPVPEKRPPEIQHFRMSDDVHSLGKVTSDLAKRRKLNSGGGLSEEL
GSARRSGEVTLTKGDPGSLEEWETVVGDDFSLYYDSYSVDERVDSDSKSEVEALTEQLSE
EEEEEEEEEEEEEEEEEEEEEEEDEESGNQSDRSGSSGRRKAKKKWRKDSPWVKPSRKRR
KREPPRAKEPRGVNGVGSSGPSEYMEVPLGSLELPSEGTLSPNHAGVSNDTSSLETERGF
EELPLCSCRMEAPKIDRISERAGHKCMATESVDGELSGCNAAILKRETMRPSSRVALMVL
CETHRARMVKHHCCPGCGYFCTAGTFLECHPDFRVAHRFHKACVSQLNGMVFCPHCGEDA
SEAQEVTIPRGDGVTPPAGTAAPAPPPLSQDVPGRADTSQPSARMRGHGEPRRPPCDPLA
DTIDSSGPSLTLPNGGCLSAVGLPLGPGREALEKALVIQESERRKKLRFHPRQLYLSVKQ
GELQKVILMLLDNLDPNFQSDQQSKRTPLHAAAQKGSVEICHVLLQAGANINAVDKQQRT
PLMEAVVNNHLEVARYMVQRGGCVYSKEEDGSTCLHHAAKIGNLEMVSLLLSTGQVDVNA
QDSGGWTPIIWAAEHKHIEVIRMLLTRGADVTLTDNEENICLHWASFTGSAAIAEVLLNA
RCDLHAVNYHGDTPLHIAARESYHDCVLLFLSRGANPELRNKEGDTAWDLTPERSDVWFA
LQLNRKLRLGVGNRAIRTEKIICRDVARGYENVPIPCVNGVDGEPCPEDYKYISENCETS
TMNIDRNITHLQHCTCVDDCSSSNCLCGQLSIRCWYDKDGRLLQEFNKIEPPLIFECNQA
CSCWRNCKNRVVQSGIKVRLQLYRTAKMGWGVRALQTIPQGTFICEYVGELISDAEADVR
EDDSYLFDLDNKDGEVYCIDARYYGNISRFINHLCDPNIIPVRVFMLHQDLRFPRIAFFS
SRDIRTGEELGFDYGDRFWDIKSKYFTCQCGSEKCKHSAEAIALEQSRLARLDPHPELLP
ELGSLPPVNT

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T36I66

Drugs and Modes of Action

Top

Preclinical Drug(s)

[+] 3 Preclinical Drugs

A-366

Drug Info

Preclinical

Solid tumour/cancer

[2]

BIX-01294

Drug Info

Preclinical

Breast cancer

[2]

MS012

Drug Info

Preclinical

Inflammation

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 7 Inhibitor drugs

A-366

Drug Info

[3]

BIX-01294

Drug Info

[4]

MS012

Drug Info

[2]

BRD9539

Drug Info

[5]

UNC0321

Drug Info

[1]

UNC0638

Drug Info

[6]

UNC0642

Drug Info

[7]

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

Structure of human G9a SET-domain (EHMT2) in complex with inhibitor 13

PDB:5VSC

Method

X-ray diffraction

Resolution

1.40 Å

Mutation

[8]

PDB Sequence

TEKIICRDVA

⁹²⁷

RGYENVPIPC

⁹³⁷

VNGVDGEPCP

⁹⁴⁷

EDYKYISENC

⁹⁵⁷

ETSTMNIDRN

⁹⁶⁷

ITHLQHCTCV

⁹⁷⁷

DDCSSSNCLC

⁹⁸⁷

GQLSIRCWYD

⁹⁹⁷

KDGRLLQEFN

¹⁰⁰⁷

KIEPPLIFEC

¹⁰¹⁷

NQACSCWRNC

¹⁰²⁷

KNRVVQSGIK

¹⁰³⁷

VRLQLYRTAK

¹⁰⁴⁷

MGWGVRALQT

¹⁰⁵⁷

IPQGTFICEY

¹⁰⁶⁷

VGELISDAEA

¹⁰⁷⁷

DVREDDSYLF

¹⁰⁸⁷

DLDEVYCIDA

¹¹⁰¹

RYYGNISRFI

¹¹¹¹

NHLCDPNIIP

¹¹²¹

VRVFMLHQDL

¹¹³¹

RFPRIAFFSS

¹¹⁴¹

RDIRTGEELG

¹¹⁵¹

FDYGDRFWDI

¹¹⁶¹

KSKYFTCQCG

¹¹⁷¹

SEKCKHSAEA

¹¹⁸¹

IALEQSRLA

Residue

Distance (Å)

ARG1044

4.530

MET1048

2.659

GLY1049

3.727

TRP1050

2.826

SER1084

3.356

TYR1085

2.791

ARG1109

3.063

PHE1110

3.639

ILE1111

3.780

ASN1112

2.878

HIS1113

2.915

Residue

Distance (Å)

LEU1114

4.935

TYR1154

3.467

PHE1158

3.732

TRP1159

4.157

LYS1162

4.658

PHE1166

3.295

THR1167

3.573

CYS1168

3.334

GLN1169

3.022

CYS1170

4.207

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

Ligand Name: Norleucine

Ligand Info

Structure Description

Structure of G9a SET-domain with Histone H3K9norLeucine mutant peptide and bound S-adenosylmethionine

PDB:5JIY

Method

X-ray diffraction

Resolution

1.48 Å

Mutation

[9]

PDB Sequence

IRTEKIICRD

⁹²⁵

VARGYENVPI

⁹³⁵

PCVNGVDGEP

⁹⁴⁵

CPEDYKYISE

⁹⁵⁵

NCETSTMNID

⁹⁶⁵

RNITHLQHCT

⁹⁷⁵

CVDDCSSSNC

⁹⁸⁵

LCGQLSIRCW

⁹⁹⁵

YDKDGRLLQE

¹⁰⁰⁵

FNKIEPPLIF

¹⁰¹⁵

ECNQACSCWR

¹⁰²⁵

NCKNRVVQSG

¹⁰³⁵

IKVRLQLYRT

¹⁰⁴⁵

AKMGWGVRAL

¹⁰⁵⁵

QTIPQGTFIC

¹⁰⁶⁵

EYVGELISDA

¹⁰⁷⁵

EADVREDDSY

¹⁰⁸⁵

LFDLDNKDGE

¹⁰⁹⁵

VYCIDARYYG

¹¹⁰⁵

NISRFINHLC

¹¹¹⁵

DPNIIPVRVF

¹¹²⁵

MLHQDLRFPR

¹¹³⁵

IAFFSSRDIR

¹¹⁴⁵

TGEELGFDYG

¹¹⁵⁵

DRFWDIKSKY

¹¹⁶⁵

FTCQCGSEKC

¹¹⁷⁵

KHSAEAIALE

¹¹⁸⁵

QSR

Residue

Distance (Å)

TYR1067

3.918

SER1084

3.771

TYR1085

4.363

LEU1086

2.702

PHE1087

3.548

Residue

Distance (Å)

ASP1088

2.900

PHE1152

4.088

TYR1154

3.423

PHE1158

4.006

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

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
DNA-binding protein RFXANK (RFXANK)	PF13606 ; PF13857	35.252 (49/139)	9.85E-16
Ankyrin repeat domain-containing protein 62 (ANKRD62)	PF13606 ; PF13857 ; PF14915 More >>	25.105 (60/239)	4.31E-09
Protein phosphatase 1 regulatory subunit 27 (PPP1R27)	PF13637	31.461 (28/89)	2.09E-07
CDK inhibitor 4C p18-INK4c (CDKN2C)	PF13637	37.234 (35/94)	6.22E-07
KN motif and ankyrin repeat domain-containing protein 4 (KANK4)	PF00023 ; PF13857 ; PF12075 More >>	26.000 (39/150)	2.09E-06
Ankyrin repeat domain-containing protein 13A (ANKRD13A)	PF13637 ; PF11904	38.095 (32/84)	3.37E-05
Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3 (ACAP3)	PF13857 ; PF01412 ; PF16746 ; PF00169 More >>	30.233 (26/86)	9.71E-05
Ankyrin repeat domain-containing protein 40 (ANKRD40)	PF13637	42.105 (24/57)	1.20E-04
Krev interaction trapped protein 1 (KRIT1)	PF13857 ; PF00373 ; PF16705 More >>	29.091 (32/110)	4.87E-04
Multiple tumor suppressor 1 (CDKN2A)		31.765 (27/85)	7.99E-04
Ankyrin repeat domain-containing protein 37 (ANKRD37)	PF13637	31.915 (30/94)	2.00E-03
Ankyrin repeat and SOCS box protein 6 (ASB6)	PF00023 ; PF07525	28.019 (58/207)	2.00E-03
Cyclin-dependent kinase 4 inhibitor B (CDKN2B)		31.111 (28/90)	2.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


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
Lysine degradation	hsa00310	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy

Degree	15	Degree centrality	1.61E-03	Betweenness centrality	6.84E-04
Closeness centrality	2.36E-01	Radiality	1.41E+01	Clustering coefficient	1.62E-01
Neighborhood connectivity	4.15E+01	Topological coefficient	9.20E-02	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-interacting Proteins

Target-interacting Proteins Info

References

Top

REF 1

Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. J Med Chem. 2010 Aug 12;53(15):5844-57.

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 and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett. 2014 Jan 2;5(2):205-9.

REF 4

Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007 Feb 9;25(3):473-81.

REF 5

A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol. 2012 Jul 20;7(7):1152-7.

REF 6

A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011 Jul 10;7(8):566-74.

REF 7

Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem. 2013 Nov 14;56(21):8931-42.

REF 8

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorg Med Chem. 2017 Aug 15;25(16):4414-4423.

REF 9

S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3. Proc Natl Acad Sci U S A. 2016 May 31;113(22):6182-7.

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