Target Information
| Target General Information | Top | |||||
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| Target ID |
T16808
(Former ID: TTDI03484)
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| Target Name |
Protein arginine methyltransferase 1 (PRMT1)
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| 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
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | 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
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.319
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| Sequence |
MAAAEAANCIMENFVATLANGMSLQPPLEEVSCGQAESSEKPNAEDMTSKDYYFDSYAHF
GIHEEMLKDEVRTLTYRNSMFHNRHLFKDKVVLDVGSGTGILCMFAAKAGARKVIGIECS SISDYAVKIVKANKLDHVVTIIKGKVEEVELPVEKVDIIISEWMGYCLFYESMLNTVLYA RDKWLAPDGLIFPDRATLYVTAIEDRQYKDYKIHWWENVYGFDMSCIKDVAIKEPLVDVV DPKQLVTNACLIKEVDIYTVKVEDLTFTSPFCLQVKRNDYVHALVAYFNIEFTRCHKRTG FSTSPESPYTHWKQTVFYMEDYLTVKTGEEIFGTIGMRPNAKNNRDLDFTIDLDFKGQLC ELSCSTDYRMR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T09K8S | |||||
| 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: 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 | No | [4] |
| PDB Sequence |
PNAEDMTSKD
51 YYFDSYAHFG61 IHEEMLKDEV71 RTLTYRNSMF81 HNRHLFKDKV91 VLDVGSGTGI 101 LCMFAAKAGA111 RKVIGIECSS121 ISDYAVKIVK131 ANKLDHVVTI141 IKGKVEEVEL 151 PVEKVDIIIS161 EWMGYCLFYE171 SMLNTVLYAR181 DKWLAPDGLI191 FPDRATLYVT 201 AIEDRQYKDY211 KIHWWENVYG221 FDMSCIKDVA231 IKEPLVDVVD241 PKQLVTNACL 251 IKEVDIYTVK261 VEDLTFTSPF271 CLQVKRNDYV281 HALVAYFNIE291 FTRCHKRTGF 301 STSPESPYTH311 WKQTVFYMED321 YLTVKTGEEI331 FGTIGMRPNA341 KNNRDLDFTI 351 DLDFKGQLCE361 LSCSTDYRMR371
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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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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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| FoxO signaling pathway | hsa04068 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Glucagon signaling pathway | hsa04922 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 6.83E-04 |
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| 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 | 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 | ||||||
| References | Top | |||||
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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 | Small molecule regulators of protein arginine methyltransferases. J Biol Chem. 2004 Jun 4;279(23):23892-9. | |||||
| REF 4 | 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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