Target Information

Target General Information

Target ID

T16808 (Former ID: TTDI03484)

Target Name

Protein arginine methyltransferase 1 (PRMT1)

Synonyms

Protein arginine N-methyltransferase 1; Interferon receptor 1-bound protein 4; IR1B4; Histone-arginine N-methyltransferase PRMT1; HRMT1L2; HMT2

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Gene Name

PRMT1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

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

Function

Constitutes the main enzyme that mediates monomethylation and asymmetric dimethylation of histone H4 'Arg-4' (H4R3me1 and H4R3me2a, respectively), a specific tag for epigenetic transcriptional activation. May be involved in the regulation of TAF15 transcriptional activity, act as an activator of estrogen receptor (ER)-mediated transactivation, play a key role in neurite outgrowth and act as a negative regulator of megakaryocytic differentiation, by modulating p38 MAPK pathway. Methylates RBM15, promoting ubiquitination and degradation of RBM15. Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity. Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Arginine methyltransferase that methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, ILF3, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15, EWS, HABP4 and SERBP1.

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BioChemical Class

Methyltransferase

UniProt ID

ANM1_HUMAN

EC Number

EC 2.1.1.319

Sequence

MAAAEAANCIMENFVATLANGMSLQPPLEEVSCGQAESSEKPNAEDMTSKDYYFDSYAHF
GIHEEMLKDEVRTLTYRNSMFHNRHLFKDKVVLDVGSGTGILCMFAAKAGARKVIGIECS
SISDYAVKIVKANKLDHVVTIIKGKVEEVELPVEKVDIIISEWMGYCLFYESMLNTVLYA
RDKWLAPDGLIFPDRATLYVTAIEDRQYKDYKIHWWENVYGFDMSCIKDVAIKEPLVDVV
DPKQLVTNACLIKEVDIYTVKVEDLTFTSPFCLQVKRNDYVHALVAYFNIEFTRCHKRTG
FSTSPESPYTHWKQTVFYMEDYLTVKTGEEIFGTIGMRPNAKNNRDLDFTIDLDFKGQLC
ELSCSTDYRMR

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3D Structure

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PDB

HIT2.0 ID

T09K8S

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

GSK3368715

Drug Info

Phase 1

Solid tumour/cancer

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 3 Inhibitor drugs

GSK3368715

Drug Info

[3]

AMI-1

Drug Info

[4]

RM65

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: GSK3368715

Ligand Info

Structure Description

type 1 PRMT in complex with the inhibitor GSK3368715

PDB:6NT2

Method

X-ray diffraction

Resolution

2.48 Å

Mutation

[5]

PDB Sequence

PNAEDMTSKD

⁵¹

YYFDSYAHFG

⁶¹

IHEEMLKDEV

⁷¹

RTLTYRNSMF

⁸¹

HNRHLFKDKV

⁹¹

VLDVGSGTGI

¹⁰¹

LCMFAAKAGA

¹¹¹

RKVIGIECSS

¹²¹

ISDYAVKIVK

¹³¹

ANKLDHVVTI

¹⁴¹

IKGKVEEVEL

¹⁵¹

PVEKVDIIIS

¹⁶¹

EWMGYCLFYE

¹⁷¹

SMLNTVLYAR

¹⁸¹

DKWLAPDGLI

¹⁹¹

FPDRATLYVT

²⁰¹

AIEDRQYKDY

²¹¹

KIHWWENVYG

²²¹

FDMSCIKDVA

²³¹

IKEPLVDVVD

²⁴¹

PKQLVTNACL

²⁵¹

IKEVDIYTVK

²⁶¹

VEDLTFTSPF

²⁷¹

CLQVKRNDYV

²⁸¹

HALVAYFNIE

²⁹¹

FTRCHKRTGF

³⁰¹

STSPESPYTH

³¹¹

WKQTVFYMED

³²¹

YLTVKTGEEI

³³¹

FGTIGMRPNA

³⁴¹

KNNRDLDFTI

³⁵¹

DLDFKGQLCE

³⁶¹

LSCSTDYRMR

³⁷¹

Residue

Distance (Å)

SER56

3.904

TYR57

3.127

ILE62

3.714

GLU65

3.090

MET66

3.890

GLU162

2.708

TRP163

3.423

MET164

3.088

GLY165

4.357

Residue

Distance (Å)

TYR166

3.621

TYR170

3.738

GLU171

3.290

MET173

3.756

HIS311

3.073

TRP312

3.888

ARG345

4.031

ASP346

4.331

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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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Protein arginine N-methyltransferase 8 (PRMT8)	PF06325	80.057 (281/351)	0.00E+00
Protein arginine methyltransferase 3 (PRMT3)	PF06325	51.466 (158/307)	8.86E-111
Protein arginine N-methyltransferase 2 (PRMT2)	PF05175 ; PF00018	35.625 (114/320)	1.82E-66
Histone-arginine methyltransferase CARM1 (CARM1)	PF11531 ; PF06325	34.969 (114/326)	1.25E-56
Protein arginine N-methyltransferase 9 (PRMT9)	PF06325	24.595 (76/309)	4.89E-15
Protein arginine methyltransferase 7 (PRMT7)	PF06325	22.781 (77/338)	3.22E-10
Protein N-lysine methyltransferase METTL21D (VCPKMT)	PF10294	32.323 (32/99)	5.00E-03
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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.

KEGG Pathway	Pathway ID	Affiliated Target
FoxO signaling pathway	hsa04068	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Glucagon signaling pathway	hsa04922	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	11	Degree centrality	1.18E-03	Betweenness centrality	6.83E-04
Closeness centrality	2.42E-01	Radiality	1.42E+01	Clustering coefficient	2.91E-01
Neighborhood connectivity	8.05E+01	Topological coefficient	1.32E-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

References

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REF 1

A novel arginine methyltransferase inhibitor with cellular activity. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4150-3.

REF 2

ClinicalTrials.gov (NCT03666988) First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL). U.S. National Institutes of Health.

REF 3

National Cancer Institute Drug Dictionary (drug name GSK6097608).

REF 4

Small molecule regulators of protein arginine methyltransferases. J Biol Chem. 2004 Jun 4;279(23):23892-9.

REF 5

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss. Cancer Cell. 2019 Jul 8;36(1):100-114.e25.

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