Target Information
Target General Information | Top | |||||
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Target ID |
T12837
(Former ID: TTDI02431)
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Target Name |
Histone-arginine methyltransferase CARM1 (CARM1)
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Synonyms |
Protein arginine N-methyltransferase 4; PRMT4; Histonearginine methyltransferase CARM1; Coactivatorassociated arginine methyltransferase 1; Coactivator-associated arginine methyltransferase 1
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Gene Name |
CARM1
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Target Type |
Literature-reported target
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[1] | ||||
Function |
Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs. Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability.
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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 |
MAAAAAAVGPGAGGAGSAVPGGAGPCATVSVFPGARLLTIGDANGEIQRHAEQQALRLEV
RAGPDSAGIALYSHEDVCVFKCSVSRETECSRVGKQSFIITLGCNSVLIQFATPNDFCSF YNILKTCRGHTLERSVFSERTEESSAVQYFQFYGYLSQQQNMMQDYVRTGTYQRAILQNH TDFKDKIVLDVGCGSGILSFFAAQAGARKIYAVEASTMAQHAEVLVKSNNLTDRIVVIPG KVEEVSLPEQVDIIISEPMGYMLFNERMLESYLHAKKYLKPSGNMFPTIGDVHLAPFTDE QLYMEQFTKANFWYQPSFHGVDLSALRGAAVDEYFRQPVVDTFDIRILMAKSVKYTVNFL EAKEGDLHRIEIPFKFHMLHSGLVHGLAFWFDVAFIGSIMTVWLSTAPTEPLTHWYQVRC LFQSPLFAKAGDTLSGTCLLIANKRQSYDISIVAQVDQTGSKSSNLLDLKNPFFRYTGTT PSPPPGSHYTSPSENMWNTGSTYNLSSGMAVAGMPTAYDLSSVIASGSSVGHNNLIPLAN TGIVNHTHSRMGSIMSTGIVQGSSGAQGSGGGSTSAHYAVNSQFTMGGPAISMASPMSIP TNTMHYGS Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
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: Tilarginine | Ligand Info | |||||
Structure Description | Crystal structure of CARM1, sinefungin, and methylated PABP1 peptide (R455) | PDB:5DX8 | ||||
Method | X-ray diffraction | Resolution | 1.94 Å | Mutation | Yes | [4] |
PDB Sequence |
RSVFSERTEE
143 SSAVQYFQFY153 GYLSQQQNMM163 QDYVRTGTYQ173 RAILQNHTDF183 KDKIVLDVGC 193 GSGILSFFAA203 QAGARKIYAV213 EASTMAQHAE223 VLVKSNNLTD233 RIVVIPGKVE 243 EVSLPEQVDI253 IISEPMGYML263 FNERMLESYL273 HAKKYLKPSG283 NMFPTIGDVH 293 LAPFTDEQLY303 MEQFTKANFW313 YQPSFHGVDL323 SALRGAAVDE333 YFRQPVVDTF 343 DIRILMAKSV353 KYTVNFLEAK363 EGDLHRIEIP373 FKFHMLHSGL383 VHGLAFWFDV 393 AFIGSIMTVW403 LSTAPTEPLT413 HWYQVRCLFQ423 SPLFAKAGDT433 LSGTCLLIAN 443 KRQSYDISIV453 AQVDQTGSKS463 SNLLDLKNPF473 FRYT
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: Sinefungin | Ligand Info | |||||
Structure Description | Crystal structure of CARM1, sinefungin, and PABP1 peptide (R455) | PDB:5DX1 | ||||
Method | X-ray diffraction | Resolution | 1.93 Å | Mutation | Yes | [4] |
PDB Sequence |
RSVFSERTEE
143 SSAVQYFQFY153 GYLSQQQNMM163 QDYVRTGTYQ173 RAILQNHTDF183 KDKIVLDVGC 193 GSGILSFFAA203 QAGARKIYAV213 EASTMAQHAE223 VLVKSNNLTD233 RIVVIPGKVE 243 EVSLPEQVDI253 IISEPMGYML263 FNERMLESYL273 HAKKYLKPSG283 NMFPTIGDVH 293 LAPFTDEQLY303 MEQFTKANFW313 YQPSFHGVDL323 SALRGAAVDE333 YFRQPVVDTF 343 DIRILMAKSV353 KYTVNFLEAK363 EGDLHRIEIP373 FKFHMLHSGL383 VHGLAFWFDV 393 AFIGSIMTVW403 LSTAPTEPLT413 HWYQVRCLFQ423 SPLFAKAGDT433 LSGTCLLIAN 443 KRQSYDISIV453 AQVDQTGSKS463 SNLLDLKNPF473 FRYT
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PHE137
3.798
TYR149
3.498
PHE150
3.659
TYR153
3.451
GLN159
3.239
MET162
3.447
MET163
4.562
ARG168
2.636
ASP190
4.235
VAL191
4.547
GLY192
2.884
CYS193
3.398
GLY194
3.634
SER195
4.778
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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 | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 2.99E-05 |
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Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 6.11E-01 |
Neighborhood connectivity | 8.71E+01 | Topological coefficient | 1.74E-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-regulating microRNAs | ||||||
Target-interacting Proteins |
References | Top | |||||
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REF 1 | 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: 1255). | |||||
REF 2 | Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1). Bioorg Med Chem Lett. 2009 Jun 1;19(11):2924-7. | |||||
REF 3 | Benzo[d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)--Hit to Lead studies. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5063-6. | |||||
REF 4 | Structural Insights into Ternary Complex Formation of Human CARM1 with Various Substrates. ACS Chem Biol. 2016 Mar 18;11(3):763-71. |
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