Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T73551 Target Info
Target Name Lysine N-methyltransferase 3A (SETD2)
Synonyms p231HBP; hSET2; SET2; SET domain-containing protein 2; Protein-lysine N-methyltransferase SETD2; KMT3A; KIAA1732; Huntingtin-interacting protein B; Huntingtin-interacting protein 1; Huntingtin yeast partner B; Histone-lysine N-methyltransferase SETD2; HYPB; HSPC069; HIP-1; HIF1
Target Type Literature-reported Target
Gene Name SETD2
Biochemical Class Methyltransferase
UniProt ID
SETD2_HUMAN
Ligand General Information  Top
Ligand Name Ademetionine Ligand Info
Canonical SMILES C[S+](CCC(C(=O)[O-])N)CC1C(C(C(O1)N2C=NC3=C(N=CN=C32)N)O)O
InChI 1S/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/t7-,8+,10+,11+,14+,27?/m0/s1
InChIKey MEFKEPWMEQBLKI-AIRLBKTGSA-N
PubChem Compound ID 34755
Drug Binding Sites of Target  Top
PDB ID: 5V21      Crystal structure of human SETD2 SET-domain in complex with H3K36M peptide and SAM
Method X-ray diffraction Resolution 2.42 Å Mutation No [1]
PDB Sequence
PSCVMDDFRD
1456
PQRWKECAKQ
1466
GKMPCYFDLI
1476
EENVYLTERQ
1498
CECTPLSKDE
1508

RAQGEIACGE
1518
DCLNRLLMIE
1528
CSSRCPNGDY
1538
CSNRRFQRKQ
1548
HADVEVILTE
1558

KKGWGLRAAK
1568
DLPSNTFVLE
1578
YCGEVLDHKE
1588
FKARVKEYAR
1598
NKNIHYYFMA
1608

LKNDEIIDAT
1618
QKGNCSRFMN
1628
HSCEPNCETQ
1638
KWTVNGQLRV
1648
GFFTTKLVPS
1658

GSELTFDYQF
1668
QRYGKEAQKC
1678
FCGSANCRGY
1688
LGGENRVSIR
1698
AAGGK
Residue
Distance (Å)
LYS1559
4.826
LYS1560
2.879
GLY1561
3.541
TRP1562
2.621
GLY1563
4.861
TYR1579
4.467
ILE1602
3.748
HIS1603
2.621
TYR1604
2.792
TYR1605
2.624
ARG1625
2.888
PHE1626
3.472
Residue
Distance (Å)
MET1627
3.760
ASN1628
2.784
HIS1629
2.964
SER1630
4.832
TYR1666
3.277
GLN1676
3.333
LYS1677
3.281
CYS1678
3.528
PHE1679
3.006
CYS1680
3.735
LEU1689
3.744
PDB ID: 7LZD      Crystal Structure of SETD2 bound to Compound 35
Method X-ray diffraction Resolution 1.80 Å Mutation No [2]
PDB Sequence
GPSCVMDDFR
1455
DPQRWKECAK
1465
QGKMPCYFDL
1475
IEENVYLTER
1485
RMQCECTPLS
1505

KDERAQGEIA
1515
CGEDCLNRLL
1525
MIECSSRCPN
1535
GDYCSNRRFQ
1545
RKQHADVEVI
1555

LTEKKGWGLR
1565
AAKDLPSNTF
1575
VLEYCGEVLD
1585
HKEFKARVKE
1595
YARNKNIHYY
1605

FMALKNDEII
1615
DATQKGNCSR
1625
FMNHSCEPNC
1635
ETQKWTVNGQ
1645
LRVGFFTTKL
1655

VPSGSELTFD
1665
YQFQRYGKEA
1675
QKCFCGSANC
1685
RGYLGGE
Residue
Distance (Å)
LYS1559
4.836
LYS1560
2.704
GLY1561
3.534
TRP1562
2.717
GLY1563
4.949
TYR1579
4.334
ILE1602
3.695
HIS1603
2.653
TYR1604
2.874
TYR1605
2.667
ARG1625
3.165
Residue
Distance (Å)
PHE1626
3.616
MET1627
3.661
ASN1628
2.804
HIS1629
2.833
SER1630
4.782
GLN1676
2.609
LYS1677
3.285
CYS1678
3.392
PHE1679
2.858
CYS1680
3.867
LEU1689
3.647
PDB ID: 7LZB      Crystal Structure of SETD2 bound to Compound 2
Method X-ray diffraction Resolution 2.28 Å Mutation No [2]
PDB Sequence
GPSCVMDDFR
1455
DPQRWKECAK
1465
QGKMPCYFDL
1475
IEENVYLTER
1485
MQCECTPLSK
1506

DERAQGEIAC
1516
GEDCLNRLLM
1526
IECSSRCPNG
1536
DYCSNRRFQR
1546
KQHADVEVIL
1556

TEKKGWGLRA
1566
AKDLPSNTFV
1576
LEYCGEVLDH
1586
KEFKARVKEY
1596
ARNKNIHYYF
1606

MALKNDEIID
1616
ATQKGNCSRF
1626
MNHSCEPNCE
1636
TQKWTVNGQL
1646
RVGFFTTKLV
1656

PSGSELTFDY
1666
QFQRYGKEAQ
1676
KCFCGSANCR
1686
GYLGG
Residue
Distance (Å)
LYS1559
4.934
LYS1560
2.774
GLY1561
3.576
TRP1562
2.538
GLY1563
4.778
TYR1579
4.552
ILE1602
3.377
HIS1603
2.634
TYR1604
2.935
TYR1605
2.551
ARG1625
3.147
Residue
Distance (Å)
PHE1626
3.690
MET1627
3.789
ASN1628
2.748
HIS1629
2.910
SER1630
4.824
GLN1676
2.935
LYS1677
3.279
CYS1678
3.496
PHE1679
2.977
CYS1680
3.928
LEU1689
3.685
PDB ID: 7TY3      Crystal Structure of SETD2 Bound to an Indole-based Inhibitor
Method X-ray diffraction Resolution 2.30 Å Mutation No [3]
PDB Sequence
GPSCVMDDFR
1455
DPQRWKECAK
1465
QGKMPCYFDL
1475
IEENVYLTER
1485
RMQCECTPLS
1505

KDERAQGEIA
1515
CGEDCLNRLL
1525
MIECSSRCPN
1535
GDYCSNRRFQ
1545
RKQHADVEVI
1555

LTEKKGWGLR
1565
AAKDLPSNTF
1575
VLEYCGEVLD
1585
HKEFKARVKE
1595
YARNKNIHYY
1605

FMALKNDEII
1615
DATQKGNCSR
1625
FMNHSCEPNC
1635
ETQKWTVNGQ
1645
LRVGFFTTKL
1655

VPSGSELTFD
1665
YQFQRYGKEA
1675
QKCFCGSANC
1685
RGYLGGEN
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SAM or .SAM2 or .SAM3 or :3SAM;style chemicals stick;color identity;select .A:1560 or .A:1561 or .A:1562 or .A:1563 or .A:1579 or .A:1602 or .A:1603 or .A:1604 or .A:1605 or .A:1625 or .A:1626 or .A:1627 or .A:1628 or .A:1629 or .A:1630 or .A:1676 or .A:1677 or .A:1678 or .A:1679 or .A:1680 or .A:1689; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS1560
2.788
GLY1561
3.735
TRP1562
2.623
GLY1563
4.890
TYR1579
4.294
ILE1602
3.690
HIS1603
2.560
TYR1604
3.206
TYR1605
2.644
ARG1625
3.181
PHE1626
3.605
Residue
Distance (Å)
MET1627
3.660
ASN1628
3.012
HIS1629
2.714
SER1630
4.617
GLN1676
2.667
LYS1677
3.417
CYS1678
3.607
PHE1679
2.918
CYS1680
3.914
LEU1689
3.526
PDB ID: 7TY2      Crystal Structure of SETD2 Bound to an Indole-based Inhibitor
Method X-ray diffraction Resolution 2.44 Å Mutation No [3]
PDB Sequence
GPSCVMDDFR
1455
DPQRWKECAK
1465
QGKMPCYFDL
1475
IEENVYLTER
1485
MQCECTPLSK
1506

DERAEIACGE
1518
DCLNRLLMIE
1528
CSSRCPNGDY
1538
CSNRRFQRKQ
1548
HADVEVILTE
1558

KKGWGLRAAK
1568
DLPSNTFVLE
1578
YCGEVLDHKE
1588
FKARVKEYAR
1598
NKNIHYYFMA
1608

LKNDEIIDAT
1618
QKGNCSRFMN
1628
HSCEPNCETQ
1638
KWTVNGQLRV
1648
GFFTTKLVPS
1658

GSELTFDYQF
1668
QRYGKEAQKC
1678
FCGSANCRGY
1688
LGGE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SAM or .SAM2 or .SAM3 or :3SAM;style chemicals stick;color identity;select .A:1560 or .A:1561 or .A:1562 or .A:1563 or .A:1579 or .A:1602 or .A:1603 or .A:1604 or .A:1605 or .A:1625 or .A:1626 or .A:1627 or .A:1628 or .A:1629 or .A:1630 or .A:1676 or .A:1677 or .A:1678 or .A:1679 or .A:1680 or .A:1689; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS1560
2.659
GLY1561
3.733
TRP1562
2.514
GLY1563
4.785
TYR1579
4.435
ILE1602
3.187
HIS1603
2.640
TYR1604
3.019
TYR1605
2.572
ARG1625
3.110
PHE1626
3.564
Residue
Distance (Å)
MET1627
3.651
ASN1628
2.898
HIS1629
2.869
SER1630
4.784
GLN1676
2.653
LYS1677
3.363
CYS1678
3.260
PHE1679
2.876
CYS1680
3.864
LEU1689
3.632
PDB ID: 7LZF      Crystal Structure of SETD2 bound to Compound 57
Method X-ray diffraction Resolution 2.47 Å Mutation No [2]
PDB Sequence
GPSCVMDDFR
1455
DPQRWKECAK
1465
QGKMPCYFDL
1475
IEENVYLTER
1485
KRMQCECTPL
1504

SKDERAQGEI
1514
ACGEDCLNRL
1524
LMIECSSRCP
1534
NGDYCSNRRF
1544
QRKQHADVEV
1554

ILTEKKGWGL
1564
RAAKDLPSNT
1574
FVLEYCGEVL
1584
DHKEFKARVK
1594
EYARNKNIHY
1604

YFMALKNDEI
1614
IDATQKGNCS
1624
RFMNHSCEPN
1634
CETQKWTVNG
1644
QLRVGFFTTK
1654

LVPSGSELTF
1664
DYQFQRYGKE
1674
AQKCFCGSAN
1684
CRGYLGGEN
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SAM or .SAM2 or .SAM3 or :3SAM;style chemicals stick;color identity;select .A:1560 or .A:1561 or .A:1562 or .A:1563 or .A:1579 or .A:1602 or .A:1603 or .A:1604 or .A:1605 or .A:1625 or .A:1626 or .A:1627 or .A:1628 or .A:1629 or .A:1630 or .A:1676 or .A:1677 or .A:1678 or .A:1679 or .A:1680 or .A:1689; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS1560
2.615
GLY1561
3.598
TRP1562
2.675
GLY1563
4.945
TYR1579
4.386
ILE1602
3.359
HIS1603
2.815
TYR1604
3.026
TYR1605
2.578
ARG1625
3.161
PHE1626
3.658
Residue
Distance (Å)
MET1627
3.624
ASN1628
2.880
HIS1629
2.615
SER1630
4.545
GLN1676
2.697
LYS1677
3.528
CYS1678
3.624
PHE1679
3.131
CYS1680
3.980
LEU1689
3.749
PDB ID: 7EA8      Human SETD2 bound to a nucleosome containing oncohistone mutations
Method Electron microscopy Resolution 3.10 Å Mutation No [4]
PDB Sequence
DDFRDPQRWK
1461
ECAKQGKMPC
1471
YFDLIEENVY
1481
LTERKKNKSH
1491
RDIKRMQCEC
1501

TPLSKDERAQ
1511
GEIACGEDCL
1521
NRLLMIECSS
1531
RCPNGDYCSN
1541
RRFQRKQHAD
1551

VEVILTEKKG
1561
WGLRAAKDLP
1571
SNTFVLEYCG
1581
EVLDHKEFKA
1591
RVKEYARNKN
1601

IHYYFMALKN
1611
DEIIDATQKG
1621
NCSRFMNHSC
1631
EPNCETQKWT
1641
VNGQLRVGFF
1651

TTKLVPSGSE
1661
LTFDYQFQRY
1671
GKEAQKCFCG
1681
SANCRGYLGG
1691
ENRVS
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SAM or .SAM2 or .SAM3 or :3SAM;style chemicals stick;color identity;select .L:1560 or .L:1561 or .L:1562 or .L:1602 or .L:1603 or .L:1604 or .L:1605 or .L:1625 or .L:1626 or .L:1627 or .L:1628 or .L:1629 or .L:1666 or .L:1676 or .L:1677 or .L:1678 or .L:1679; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS1560
3.125
GLY1561
4.860
TRP1562
3.782
ILE1602
3.644
HIS1603
1.430
TYR1604
2.586
TYR1605
2.959
ARG1625
2.975
PHE1626
3.399
Residue
Distance (Å)
MET1627
3.421
ASN1628
3.441
HIS1629
4.009
TYR1666
3.388
GLN1676
2.680
LYS1677
2.771
CYS1678
3.170
PHE1679
4.241
References  Top
REF 1 Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. Sci Rep. 2017 Mar 3;7:43906.
REF 2 Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies. ACS Med Chem Lett. 2021 Aug 24;12(10):1539-1545.
REF 3 Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies. ACS Med Chem Lett. 2022 Jun 7;13(7):1137-1143.
REF 4 Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations. Cell Discov. 2021 May 11;7(1):32.

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