Target Information
Target General Information | Top | |||||
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Target ID |
T04980
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Target Name |
EZH2 Y641N mutant (EZH2 Y641N)
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Synonyms |
Lysine Nmethyltransferase 6 Y641N mutant; Lysine N-methyltransferase 6 Y641N mutant; KMT6 Y641N mutant; Histonelysine Nmethyltransferase EZH2 Y641N mutant; Histone-lysine N-methyltransferase EZH2 Y641N mutant; EZH2 Y641N mutations; ENX1 Y641N mutant; ENX-1 Y641N mutant
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Gene Name |
EZH2
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Target Type |
Patented-recorded target
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[1] | ||||
Function |
Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription. Polycomb group (PcG) protein.
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UniProt ID | ||||||
EC Number |
EC 2.1.1.43
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Sequence |
MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEW
KQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNF MVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQ YNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEEL KEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFH ATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPN NSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKM KPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPA PAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQ NFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVS CKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDK YMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGE ELFFDYRYSQADALKYVGIEREMEIP Click to Show/Hide
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Drug Binding Sites of Target | Top | |||||
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Ligand Name: 5,8-Dichloro-2-[(4-Ethyl-6-Methyl-2-Oxo-1,2-Dihydropyridin-3-Yl)methyl]-7-({1-[(2r)-2-Hydroxypropanoyl]piperidin-4-Yl}oxy)-3,4-Dihydroisoquinolin-1(2h)-One | Ligand Info | |||||
Structure Description | Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor | PDB:5IJ8 | ||||
Method | X-ray diffraction | Resolution | 2.99 Å | Mutation | Yes | [2] |
PDB Sequence |
EKGPICWRKR
18 VKSEYMRLRQ28 LKRFRRADEV38 KSMFNSNRQK48 IQERTEILNQ58 EWKQRRIQPV 68 HIMRECSVTS87 DLDFPKQVIP97 LKTLNAVASV107 PIMYSWSPLQ117 QNFMVEDIND 168 EIFVELVNAL178 GQLDRRDEKP219 SDKIFEAISS229 MFPDKGTAEE239 LKEKYKECTP 262 NIDGPNAKSV272 QREQSLHSFH282 TLFCRRCFKY292 DCFLHPFHAT302 PNTYKRWSGA 435 EASMFRVLIG445 TYYDNFCAIA455 RLIGTKTCRQ465 VYEFRVKVYN519 YQPCDHPRQP 529 CDNSCPCVIA539 QNFCEKFCQC549 SSECQNRFPG559 CRCKAQCNTK569 QCPCYLAVRE 579 CDPDLCLTCG589 AADHWDSKNV599 SCKNCSIQRG609 SKKHLLLAPS619 DVAGWGIFIK 629 DPVQKNEFIS639 ENCGEIISQD649 EADRRGKVYD659 KYMCSFLFNL669 NNDFVVDATR 679 KGNKIRFANH689 SVNPNCYAKV699 MMVNGDHRIG709 IFAKRAIQTG719 EELFFDYRYS 729 QADA
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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 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).
Human Pathway Affiliation
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Lysine degradation | hsa00310 | Affiliated Target |
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Class: Metabolism => Amino acid metabolism | Pathway Hierarchy |
References | Top | |||||
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REF 1 | EZH2 inhibitors: a patent review (2014-2016).Expert Opin Ther Pat. 2017 Jul;27(7):797-813. | |||||
REF 2 | Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. Nat Commun. 2016 Apr 28;7:11384. |
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