Target Information
Target General Information | Top | |||||
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Target ID |
T69200
(Former ID: TTDI03566)
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Target Name |
Mitotic growth and transcription activator (BAF190A)
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Synonyms |
Transcription activator BRG1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4; SNF2L4; SNF2B; SNF2-beta; Protein brahma homolog 1; Protein BRG-1; BRG1-associated factor 190A; BRG1; ATP-dependent helicase SMARCA4
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Gene Name |
SMARCA4
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Target Type |
Literature-reported target
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[1] | ||||
Function |
Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium-dependent release of a repressor complex and the recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by SMARCA4-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves the release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development, a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues. Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1. Binds via DLX1 to enhancers located in the intergenic region between DLX5 and DLX6 and this binding is stabilized by the long non-coding RNA (lncRNA) Evf2. Binds to RNA in a promiscuous manner. Binding to RNAs including lncRNA Evf2 leads to inhibition of SMARCA4 ATPase and chromatin remodeling activities. Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
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BioChemical Class |
Acid anhydride hydrolase
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UniProt ID | ||||||
EC Number |
EC 3.6.4.-
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Sequence |
MSTPDPPLGGTPRPGPSPGPGPSPGAMLGPSPGPSPGSAHSMMGPSPGPPSAGHPIPTQG
PGGYPQDNMHQMHKPMESMHEKGMSDDPRYNQMKGMGMRSGGHAGMGPPPSPMDQHSQGY PSPLGGSEHASSPVPASGPSSGPQMSSGPGGAPLDGADPQALGQQNRGPTPFNQNQLHQL RAQIMAYKMLARGQPLPDHLQMAVQGKRPMPGMQQQMPTLPPPSVSATGPGPGPGPGPGP GPGPAPPNYSRPHGMGGPNMPPPGPSGVPPGMPGQPPGGPPKPWPEGPMANAAAPTSTPQ KLIPPQPTGRPSPAPPAVPPAASPVMPPQTQSPGQPAQPAPMVPLHQKQSRITPIQKPRG LDPVEILQEREYRLQARIAHRIQELENLPGSLAGDLRTKATIELKALRLLNFQRQLRQEV VVCMRRDTALETALNAKAYKRSKRQSLREARITEKLEKQQKIEQERKRRQKHQEYLNSIL QHAKDFKEYHRSVTGKIQKLTKAVATYHANTEREQKKENERIEKERMRRLMAEDEEGYRK LIDQKKDKRLAYLLQQTDEYVANLTELVRQHKAAQVAKEKKKKKKKKKAENAEGQTPAIG PDGEPLDETSQMSDLPVKVIHVESGKILTGTDAPKAGQLEAWLEMNPGYEVAPRSDSEES GSEEEEEEEEEEQPQAAQPPTLPVEEKKKIPDPDSDDVSEVDARHIIENAKQDVDDEYGV SQALARGLQSYYAVAHAVTERVDKQSALMVNGVLKQYQIKGLEWLVSLYNNNLNGILADE MGLGKTIQTIALITYLMEHKRINGPFLIIVPLSTLSNWAYEFDKWAPSVVKVSYKGSPAA RRAFVPQLRSGKFNVLLTTYEYIIKDKHILAKIRWKYMIVDEGHRMKNHHCKLTQVLNTH YVAPRRLLLTGTPLQNKLPELWALLNFLLPTIFKSCSTFEQWFNAPFAMTGEKVDLNEEE TILIIRRLHKVLRPFLLRRLKKEVEAQLPEKVEYVIKCDMSALQRVLYRHMQAKGVLLTD GSEKDKKGKGGTKTLMNTIMQLRKICNHPYMFQHIEESFSEHLGFTGGIVQGLDLYRASG KFELLDRILPKLRATNHKVLLFCQMTSLMTIMEDYFAYRGFKYLRLDGTTKAEDRGMLLK TFNEPGSEYFIFLLSTRAGGLGLNLQSADTVIIFDSDWNPHQDLQAQDRAHRIGQQNEVR VLRLCTVNSVEEKILAAAKYKLNVDQKVIQAGMFDQKSSSHERRAFLQAILEHEEQDESR HCSTGSGSASFAHTAPPPAGVNPDLEEPPLKEEDEVPDDETVNQMIARHEEEFDLFMRMD LDRRREEARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKMFGRGSRHRKEVDYS DSLTEKQWLKAIEEGTLEEIEEEVRQKKSSRKRKRDSDAGSSTPTTSTRSRDKDDESKKQ KKRGRPPAEKLSPNPPNLTKKMKKIVDAVIKYKDSSSGRQLSEVFIQLPSRKELPEYYEL IRKPVDFKKIKERIRNHKYRSLNDLEKDVMLLCQNAQTFNLEGSLIYEDSIVLQSVFTSV RQKIEKEDDSEGEESEEEEEGEEEGSESESRSVKVKIKLGRKEKAQDRLKGGRRRPSRGS RAKPVVSDDDSEEEQEEDRSGSGSEED Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
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 diphosphate | Ligand Info | |||||
Structure Description | The motor-nucleosome module of human chromatin remodeling PBAF-nucleosome complex | PDB:7VDT | ||||
Method | Electron microscopy | Resolution | 2.80 Å | Mutation | No | [2] |
PDB Sequence |
KLIDQKKDKR
549 LAYLLQQTDE559 YYAVAHAVTE740 RVDKQSALMV750 NGVLKQYQIK760 GLEWLVSLYN 770 NNLNGILADE780 MGLGKTIQTI790 ALITYLMEHK800 RINGPFLIIV810 PLSTLSNWAY 820 EFDKWAPSVV830 KVSYKGSPAA840 RRAFVPQLRS850 GKFNVLLTTY860 EYIIKDKHIL 870 AKIRWKYMIV880 DEGHRMKNHH890 CKLTQVLNTH900 YVAPRRLLLT910 GTPLQNKLPE 920 LWALLNFLLP930 TIFKSCSTFE940 QWFNAPFAMT950 GEKVDLNEEE960 TILIIRRLHK 970 VLRPFLLRRL980 KKEVEAQLPE990 KVEYVIKCDM1000 SALQRVLYRH1010 MQAKGVLLTD 1020 GSGTKTLMNT1038 IMQLRKICNH1048 PYMFQHIEES1058 FSEHLGFTGG1068 IVQGLDLYRA 1078 SGKFELLDRI1088 LPKLRATNHK1098 VLLFCQMTSL1108 MTIMEDYFAY1118 RGFKYLRLDG 1128 TTKAEDRGML1138 LKTFNEPGSE1148 YFIFLLSTRA1158 GGLGLNLQSA1168 DTVIIFDSDW 1178 NPHQDLQAQD1188 RAHRIGQQNE1198 VRVLRLCTVN1208 SVEEKILAAA1218 KYKLNVDQKV 1228 IQAGMFDQKS1238 SSHERRAFLQ1248 AILEHEEQDE1258 EEDEVPDDET1268 VNQMIARHEE 1278 EFDLFMRMDL1288 DRRREEARNP1298 KRKPRLMEED1308 ELPSWIIKEK1332 MFGRGSRHRK 1342 EVDYSDS
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Ligand Name: PFI-3 | Ligand Info | |||||
Structure Description | Crystal structure of the bromodomain of human BRG1 (SMARCA4) in complex with PFI-3 chemical probe | PDB:5DKD | ||||
Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
PDB Sequence |
NLTKKMKKIV
1466 DAVIKYKDSS1476 SGRQLSEVFI1486 QLPSRKELPE1496 YYELIRKPVD1506 FKKIKERIRN 1516 HKYRSLNDLE1526 KDVMLLCQNA1536 QTFNLEGSLI1546 YEDSIVLQSV1556 FTSVRQKIEK 1566
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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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Thermogenesis | hsa04714 | Affiliated Target |
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Class: Organismal Systems => Environmental adaptation | Pathway Hierarchy |
Degree | 57 | Degree centrality | 6.12E-03 | Betweenness centrality | 3.95E-03 |
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Closeness centrality | 2.60E-01 | Radiality | 1.45E+01 | Clustering coefficient | 1.86E-01 |
Neighborhood connectivity | 4.08E+01 | Topological coefficient | 4.03E-02 | 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 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: 2740). | |||||
REF 2 | Structure of human chromatin-remodelling PBAF complex bound to a nucleosome. Nature. 2022 May;605(7908):166-171. | |||||
REF 3 | Crystal structure of the bromodomain of human BRG1 (SMARCA4) in complex with PFI-3 chemical probe |
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