Target Information
| Target General Information | Top | |||||
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| Target ID |
T82665
(Former ID: TTDI03486)
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| Target Name |
Protein arginine methyltransferase 5 (PRMT5)
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| Synonyms |
Shk1 kinase-binding protein 1 homolog; SKB1Hs; SKB1 homolog; SKB1; Protein arginine N-methyltransferase 5; Jak-binding protein 1; JBP1; IBP72; Histone-arginine N-methyltransferase PRMT5; HRMT1L5; 72 kDa ICln-binding protein
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| Gene Name |
PRMT5
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 3 | Brain cancer [ICD-11: 2A00] | |||||
| 4 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 5 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| Function |
Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H and may regulate its transcriptional elongation properties. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Methylates GM130/GOLGA2, regulating Golgi ribbon formation. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression. Symmetrically methylates NCL. Methylates TP53; methylation might possibly affect TP53 target gene specificity. Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.320
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| Sequence |
MAAMAVGGAGGSRVSSGRDLNCVPEIADTLGAVAKQGFDFLCMPVFHPRFKREFIQEPAK
NRPGPQTRSDLLLSGRDWNTLIVGKLSPWIRPDSKVEKIRRNSEAAMLQELNFGAYLGLP AFLLPLNQEDNTNLARVLTNHIHTGHHSSMFWMRVPLVAPEDLRDDIIENAPTTHTEEYS GEEKTWMWWHNFRTLCDYSKRIAVALEIGADLPSNHVIDRWLGEPIKAAILPTSIFLTNK KGFPVLSKMHQRLIFRLLKLEVQFIITGTNHHSEKEFCSYLQYLEYLSQNRPPPNAYELF AKGYEDYLQSPLQPLMDNLESQTYEVFEKDPIKYSQYQQAIYKCLLDRVPEEEKDTNVQV LMVLGAGRGPLVNASLRAAKQADRRIKLYAVEKNPNAVVTLENWQFEEWGSQVTVVSSDM REWVAPEKADIIVSELLGSFADNELSPECLDGAQHFLKDDGVSIPGEYTSFLAPISSSKL YNEVRACREKDRDPEAQFEMPYVVRLHNFHQLSAPQPCFTFSHPNRDPMIDNNRYCTLEF PVEVNTVLHGFAGYFETVLYQDITLSIRPETHSPGMFSWFPILFPIKQPITVREGQTICV RFWRCSNSKKVWYEWAVTAPVCSAIHNPTGRSYTIGL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T14BVD | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | GSK3326595 | Drug Info | Phase 2 | Breast cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | GSK3326595 | Drug Info | [1] | |||
| 2 | cmp5 | Drug Info | [8] | |||
| 3 | DS-437 | Drug Info | [9] | |||
| 4 | EPZ015666 | Drug Info | [10] | |||
| 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: Adenosine | Ligand Info | |||||
| Structure Description | PRMT5:MEP50 complexed with adenosine | PDB:7MXC | ||||
| Method | X-ray diffraction | Resolution | 2.41 Å | Mutation | No | [11] |
| PDB Sequence |
RVSSGRDLNC
22 VPEIADTLGA32 VAKQGFDFLC42 MPVFHPRFKR52 EFIQEPAKNR62 PGPQTRSDLL 72 LSGRDWNTLI82 VGKLSPWIRP92 DSKVEKIRRN102 SEAAMLQELN112 FGAYLGLPAF 122 LLPLNQEDNT132 NLARVLTNHI142 HTGHHSSMFW152 MRVPLVAPED162 LRDDIIENAP 172 TTHTEEYSGE182 EKTWMWWHNF192 RTLCDYSKRI202 AVALEIGADL212 PSNHVIDRWL 222 GEPIKAAILP232 TSIFLTNKKG242 FPVLSKMHQR252 LIFRLLKLEV262 QFIITGTNHH 272 SCSYLQYLEY286 LSQNRPPPNA296 YELFAKGYED306 YLQSPLQPLM316 DNLESQTYEV 326 FEKDPIKYSQ336 YQQAIYKCLL346 DRVPEEEKDT356 NVQVLMVLGA366 GRGPLVNASL 376 RAAKQADRRI386 KLYAVEKNPN396 AVVTLENWQF406 EEWGSQVTVV416 SSDMREWVAP 426 EKADIIVSEL436 LGSFADNELS446 PECLDGAQHF456 LKDDGVSIPG466 EYTSFLAPIS 476 SSKLYNEVRA486 CREKDRDPEA496 QFEMPYVVRL506 HNFHQLSAPQ516 PCFTFSHPNR 526 DPMIDNNRYC536 TLEFPVEVNT546 VLHGFAGYFE556 TVLYQDITLS566 IRPETHSPGM 576 FSWFPILFPI586 KQPITVREGQ596 TICVRFWRCS606 NSKKVWYEWA616 VTAPVCSAIH 626 NPTGRSYTIG636 L
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PRO314
3.418
LEU315
3.355
ASP317
4.989
LEU319
4.619
TYR324
2.722
LEU364
4.985
GLY365
3.172
ALA366
4.725
GLY367
3.705
VAL391
4.570
GLU392
2.638
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| Ligand Name: Ademetionine | Ligand Info | |||||
| Structure Description | Crystal structure of PRMT5:MEP50 with Compound 10 and SAM | PDB:5EML | ||||
| Method | X-ray diffraction | Resolution | 2.39 Å | Mutation | No | [12] |
| PDB Sequence |
RVSSGRDLNC
22 VPEIADTLGA32 VAKQGFDFLC42 MPVFHPRFKR52 EFIQEPAKNR62 PGPQTRSDLL 72 LSGRDWNTLI82 VGKLSPWIRP92 DSKVEKIRRN102 SEAAMLQELN112 FGAYLGLPAF 122 LLPLNQEDNT132 NLARVLTNHI142 HTGHHSSMFW152 MRVPLVAPED162 LRDDIIENAP 172 TTHTEEYSGE182 EKTWMWWHNF192 RTLCDYSKRI202 AVALEIGADL212 PSNHVIDRWL 222 GEPIKAAILP232 TSIFLTNKKG242 FPVLSKMHQR252 LIFRLLKLEV262 QFIITGTNHH 272 SEKEFCSYLQ282 YLEYLSQNRP292 PPNAYELFAK302 GYEDYLQSPL312 QPLMDNLESQ 322 TYEVFEKDPI332 KYSQYQQAIY342 KCLLDRVPEE352 EKDTNVQVLM362 VLGAGRGPLV 372 NASLRAAKQA382 DRRIKLYAVE392 KNPNAVVTLE402 NWQFEEWGSQ412 VTVVSSDMRE 422 WVAPEKADII432 VSELLGSFAD442 NELSPECLDG452 AQHFLKDDGV462 SIPGEYTSFL 472 APISSSKLYN482 EVRACREKDR492 DPEAQFEMPY502 VVRLHNFHQL512 SAPQPCFTFS 522 HPNRDPMIDN532 NRYCTLEFPV542 EVNTVLHGFA552 GYFETVLYQD562 ITLSIRPETH 572 SPGMFSWFPI582 LFPIKQPITV592 REGQTICVRF602 WRCSNSKKVW612 YEWAVTAPVC 622 SAIHNPTGRS632 YTIGL
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PRO314
3.620
LEU315
3.703
LEU319
4.363
TYR324
2.453
GLU328
4.221
LYS333
2.854
TYR334
2.811
LEU364
4.704
GLY365
3.181
ALA366
4.098
GLY367
3.650
PRO370
3.193
LEU371
3.518
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| 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 |
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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).
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
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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| Degree | 24 | Degree centrality | 2.58E-03 | Betweenness centrality | 2.44E-03 |
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| Closeness centrality | 2.45E-01 | Radiality | 1.43E+01 | Clustering coefficient | 1.99E-01 |
| Neighborhood connectivity | 5.90E+01 | Topological coefficient | 8.19E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT05094336) A Phase 1/1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 193 Alone and in Combination With Docetaxel in Subjects With Advanced MTAP-null Solid Tumors. U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT04676516) A Phase II Window of Opportunity Trial of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer (OTT-19-06). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03886831) A Study of PRT543 in Participants With Advanced Solid Tumors and Hematologic Malignancies. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04089449) A Study of PRT811 in Participants With Advanced Solid Tumors, CNS Lymphoma and Gliomas. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT03854227) A Dose Escalation Study Of PF-06939999 In Participants With Advanced Or Metastatic Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT03573310) A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS. U.S. National Institutes of Health. | |||||
| REF 8 | Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood. 2015 Apr 16;125(16):2530-43. | |||||
| REF 9 | Discovery of a Dual PRMT5-PRMT7 Inhibitor. ACS Med Chem Lett. 2015 Mar 2;6(4):408-12. | |||||
| REF 10 | 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: 1256). | |||||
| REF 11 | SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance. Mol Cancer Ther. 2022 Jan;21(1):3-15. | |||||
| REF 12 | Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett. 2015 Dec 2;7(2):162-6. | |||||
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