Binding Site Information of Target
Target General Information | Top | ||||
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Target ID | T08326 | Target Info | |||
Target Name | Cyclin-dependent kinase 12 (CDK12) | ||||
Synonyms | Cdc2-related kinase, arginine/serine-rich; CrkRS; Cell division cycle 2-related protein kinase 7; CDC2-related protein kinase 7; Cell division protein kinase 12; hCDK12 | ||||
Target Type | Clinical trial Target | ||||
Gene Name | CDK12 | ||||
Biochemical Class | Kinase | ||||
UniProt ID |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: adenosine diphosphate | Ligand Info | |||||
Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | PDB:4NST | ||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [1] |
PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDGAFYLVF813 EYMDHDLMGL823 LESGLVHFSE 833 DHIKSFMKQL843 MEGLEYCHKK853 NFLHRDIKCS863 NILLNNSGQI873 KLADFGLARL 883 YNSEESRPYN894 KVITLWYRPP904 ELLLGEERYT914 PAIDVWSCGC924 ILGELFTKKP 934 IFQANLELAQ944 LELISRLCGS954 PCPAVWPDVI964 KLPYFNTMKP974 KKQYRRRLRE 984 EFSFIPSAAL994 DLLDHMLTLD1004 PSKRCTAEQT1014 LQSDFLKDVE1024 LSKMAPPDLP 1034 HWQDCHELWS1044 KK
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ILE733
3.461
GLY734
4.155
GLU735
3.234
GLY736
2.961
THR737
2.914
VAL741
3.881
ALA754
3.255
LYS756
2.791
GLU774
4.822
VAL787
4.458
PHE813
3.304
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Ligand Name: Phosphonothreonine | Ligand Info | |||||
Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | PDB:4NST | ||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [1] |
PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDGAFYLVF813 EYMDHDLMGL823 LESGLVHFSE 833 DHIKSFMKQL843 MEGLEYCHKK853 NFLHRDIKCS863 NILLNNSGQI873 KLADFGLARL 883 YNSEESRPYN894 KVITLWYRPP904 ELLLGEERYT914 PAIDVWSCGC924 ILGELFTKKP 934 IFQANLELAQ944 LELISRLCGS954 PCPAVWPDVI964 KLPYFNTMKP974 KKQYRRRLRE 984 EFSFIPSAAL994 DLLDHMLTLD1004 PSKRCTAEQT1014 LQSDFLKDVE1024 LSKMAPPDLP 1034 HWQDCHELWS1044 KK
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: AMP-PNP | Ligand Info | |||||
Structure Description | Crystal structure of the human CDK12-cyclin K complex bound to AMPPNP | PDB:4CXA | ||||
Method | X-ray diffraction | Resolution | 3.15 Å | Mutation | No | [2] |
PDB Sequence |
DWGKRCVDKF
727 DIIGIIGEGT737 YGQVYKAKDK747 DTGELVALKK757 VRLDNEKEGF767 PITAIREIKI 777 LRQLIHRSVV787 NMKEIVTDKQ797 LDFKKDKGAF809 YLVFEYMDHD819 LMGLLESGLV 829 HFSEDHIKSF839 MKQLMEGLEY849 CHKKNFLHRD859 IKCSNILLNN869 SGQIKLADFG 879 LARLYNSEER890 PYNKVITLWY901 RPPELLLGEE911 RYTPAIDVWS921 CGCILGELFT 931 KKPIFQANLE941 LAQLELISRL951 CGSPCPAVWP961 DVIKLPYFNT971 MKPKKQYRRR 981 LREEFSFIPS991 AALDLLDHML1001 TLDPSKRCTA1011 EQTLQSDFLK1021 DVELSKMAPP 1031 DLPHWQDCHE1041 LWSKKRRRQ
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .A:733 or .A:735 or .A:736 or .A:737 or .A:741 or .A:754 or .A:756 or .A:774 or .A:787 or .A:813 or .A:814 or .A:815 or .A:816 or .A:819 or .A:859 or .A:861 or .A:863 or .A:864 or .A:866 or .A:876 or .A:877 or .A:1040 or .A:1041; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ILE733
4.015
GLU735
4.302
GLY736
3.284
THR737
3.117
VAL741
3.865
ALA754
3.344
LYS756
3.144
GLU774
4.751
VAL787
4.428
PHE813
3.632
GLU814
3.372
TYR815
3.996
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Ligand Name: Aluminum fluoride | Ligand Info | |||||
Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | PDB:4NST | ||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [1] |
PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDGAFYLVF813 EYMDHDLMGL823 LESGLVHFSE 833 DHIKSFMKQL843 MEGLEYCHKK853 NFLHRDIKCS863 NILLNNSGQI873 KLADFGLARL 883 YNSEESRPYN894 KVITLWYRPP904 ELLLGEERYT914 PAIDVWSCGC924 ILGELFTKKP 934 IFQANLELAQ944 LELISRLCGS954 PCPAVWPDVI964 KLPYFNTMKP974 KKQYRRRLRE 984 EFSFIPSAAL994 DLLDHMLTLD1004 PSKRCTAEQT1014 LQSDFLKDVE1024 LSKMAPPDLP 1034 HWQDCHELWS1044 KK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AF3 or .AF32 or .AF33 or :3AF3;style chemicals stick;color identity;select .A:737 or .A:859 or .A:861 or .A:863 or .A:864 or .A:877; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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Ligand Name: N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-{trans-4-[(quinazolin-2-yl)amino]cyclohexyl}acetamide | Ligand Info | |||||
Structure Description | Structure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide | PDB:6CKX | ||||
Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [3] |
PDB Sequence |
RCVDKFDIIG
731 IIGEGTYGQV741 YKAKDKDTGE751 LVALKKVRLD761 NEKEGFPITA771 IREIKILRQL 781 IHRSVVNMKE791 IVTDKGAFYL811 VFEYMDHDLM821 GLLESGLVHF831 SEDHIKSFMK 841 QLMEGLEYCH851 KKNFLHRDIK861 CSNILLNNSG871 QIKLADFGLA881 RLYNSEESRP 891 YNKVITLWYR902 PPELLLGEER912 YTPAIDVWSC922 GCILGELFTK932 KPIFQANLEL 942 AQLELISRLC952 GSPCPAVWPD962 VIKLPYFNTM972 KPKKQYRRRL982 REEFSFIPSA 992 ALDLLDHMLT1002 LDPSKRCTAE1012 QTLQSDFLKD1022 VE
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .8M1 or .8M12 or .8M13 or :38M1;style chemicals stick;color identity;select .A:732 or .A:733 or .A:734 or .A:735 or .A:741 or .A:754 or .A:756 or .A:787 or .A:813 or .A:814 or .A:815 or .A:816 or .A:817 or .A:818 or .A:819 or .A:822 or .A:866; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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Ligand Name: (E)-N-[4-[(1R,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]oxyphenyl]-4-(dimethylamino)but-2-enamide | Ligand Info | |||||
Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with the inhibitor BSJ-01-175 | PDB:7NXK | ||||
Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [4] |
PDB Sequence |
TESDWGKRCV
724 DKFDIIGIIG734 EGTYGQVYKA744 KDKDTGELVA754 LKKVRLDNEK764 EGFPITAIRE 774 IKILRQLIHR784 SVVNMKEIVT794 DKQDKKDKGA808 FYLVFEYMDH818 DLMGLLESGL 828 VHFSEDHIKS838 FMKQLMEGLE848 YCHKKNFLHR858 DIKCSNILLN868 NSGQIKLADF 878 GLARLYNSEE888 SRPYNKVITL899 WYRPPELLLG909 EERYTPAIDV919 WSCGCILGEL 929 FTKKPIFQAN939 LELAQLELIS949 RLCGSPCPAV959 WPDVIKLPYF969 NTMKPKKQYR 979 RRLREEFSFI989 PSAALDLLDH999 MLTLDPSKRC1009 TAEQTLQSDF1019 LKDVELSKMA 1029 PPDLPHWQDC1039 H
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .UUB or .UUB2 or .UUB3 or :3UUB;style chemicals stick;color identity;select .A:732 or .A:733 or .A:734 or .A:735 or .A:736 or .A:741 or .A:754 or .A:756 or .A:813 or .A:814 or .A:815 or .A:816 or .A:817 or .A:818 or .A:819 or .A:866 or .A:876 or .A:877 or .A:1037 or .A:1038 or .A:1039 or .A:1040; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ILE732
4.923
ILE733
2.886
GLY734
3.665
GLU735
3.521
GLY736
3.751
VAL741
3.285
ALA754
3.540
LYS756
4.632
PHE813
3.816
GLU814
3.733
TYR815
3.915
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Ligand Name: (2R)-2-({9-(1-methylethyl)-6-[(4-pyridin-2-ylbenzyl)amino]-9H-purin-2-yl}amino)butan-1-ol | Ligand Info | |||||
Structure Description | Structure of DDB1 bound to CR8-engaged CDK12-cyclinK | PDB:6TD3 | ||||
Method | X-ray diffraction | Resolution | 3.46 Å | Mutation | Yes | [5] |
PDB Sequence |
TESDWGKRCV
724 DKFDIIGIIG734 EGTYGQVYKA744 KDKDTGELVA754 LKKVRLDNEK764 EGFPITAIRE 774 IKILRQLIHR784 SVVNMKEIVT794 DKQDALDFKK804 DKGAFYLVFE814 YMDHDLMGLL 824 ESGLVHFSED834 HIKSFMKQLM844 EGLEYCHKKN854 FLHRDIKCSN864 ILLNNSGQIK 874 LADFGLARLY884 NSEESRPYNK895 VITLWYRPPE905 LLLGEERYTP915 AIDVWSCGCI 925 LGELFTKKPI935 FQANLELAQL945 ELISRLCGSP955 CPAVWPDVIR965 LPYFNTMKPK 975 KQYRRRLREE985 FSFIPSAALD995 LLDHMLTLDP1005 SKRCTAEQTL1015 QSDFLKDVEL 1025 SKMAPPDLPH1035 WQDCHELWSK1045 KR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .RC8 or .RC82 or .RC83 or :3RC8;style chemicals stick;color identity;select .B:732 or .B:733 or .B:734 or .B:735 or .B:736 or .B:741 or .B:743 or .B:754 or .B:755 or .B:756 or .B:774 or .B:787 or .B:813 or .B:814 or .B:815 or .B:816 or .B:817 or .B:818 or .B:819 or .B:863 or .B:864 or .B:866 or .B:867 or .B:876 or .B:877; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ILE732
4.112
ILE733
2.762
GLY734
3.113
GLU735
4.526
GLY736
3.544
VAL741
2.384
LYS743
3.464
ALA754
2.254
LEU755
4.407
LYS756
2.381
GLU774
4.481
VAL787
2.792
PHE813
2.336
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Ligand Name: N-[4-[(3r)-3-[[5-Chloranyl-4-(1h-Indol-3-Yl)pyrimidin-2-Yl]amino]piperidin-1-Yl]carbonylphenyl]-4-(Dimethylamino)butanamide | Ligand Info | |||||
Structure Description | Crystal Structure of the Human Cdk12-Cyclink Complex | PDB:5ACB | ||||
Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [6] |
PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDALDFKKD805 KGAFYLVFEY815 MDHDLMGLLE 825 SGLVHFSEDH835 IKSFMKQLME845 GLEYCHKKNF855 LHRDIKCSNI865 LLNNSGQIKL 875 ADFGLARLYN885 SEESRPYNKV896 ITLWYRPPEL906 LLGEERYTPA916 IDVWSCGCIL 926 GELFTKKPIF936 QANLELAQLE946 LISRLCGSPC956 PAVWPDVIKL966 PYFNTMKPKK 976 QYRRRLREEF986 SFIPSAALDL996 LDHMLTLDPS1006 KRCTAEQTLQ1016 SDFLKDVELS 1026 KMAPPDLPHW1036 QDCH
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5I1 or .5I12 or .5I13 or :35I1;style chemicals stick;color identity;select .C:730 or .C:732 or .C:733 or .C:734 or .C:735 or .C:736 or .C:741 or .C:743 or .C:754 or .C:756 or .C:787 or .C:813 or .C:814 or .C:815 or .C:816 or .C:817 or .C:818 or .C:819 or .C:866 or .C:877 or .C:1037 or .C:1039; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ILE730
4.700
ILE732
4.021
ILE733
3.613
GLY734
4.302
GLU735
3.670
GLY736
4.423
VAL741
3.664
LYS743
3.560
ALA754
3.359
LYS756
3.607
VAL787
4.239
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Ligand Name: 2-[(2S)-1-(6-{[(4,5-difluoro-1H-benzimidazol-2-yl)methyl]amino}-9-ethyl-9H-purin-2-yl)piperidin-2-yl]ethan-1-ol | Ligand Info | |||||
Structure Description | Crystal structure of human CDK12/CyclinK in complex with an inhibitor | PDB:6B3E | ||||
Method | X-ray diffraction | Resolution | 3.06 Å | Mutation | No | [7] |
PDB Sequence |
SDWGKRCVDK
726 FDIIGIIGEG736 TYGQVYKAKD746 KDTGELVALK756 KVRLDNEKEG766 FPITAIREIK 776 ILRQLIHRSV786 VNMKEIVTDK796 GAFYLVFEYM816 DHDLMGLLES826 GLVHFSEDHI 836 KSFMKQLMEG846 LEYCHKKNFL856 HRDIKCSNIL866 LNNSGQIKLA876 DFGLARLYNS 886 EESRPYNKVI897 TLWYRPPELL907 LGEERYTPAI917 DVWSCGCILG927 ELFTKKPIFQ 937 ANLELAQLEL947 ISRLCGSPCP957 AVWPDVIKLP967 YFNTMKPKKQ977 YRRRLREEFS 987 FIPSAALDLL997 DHMLTLDPSK1007 RCTAEQTLQS1017 DFLKDVELSK1027 MAPPDLPHW |
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CJM or .CJM2 or .CJM3 or :3CJM;style chemicals stick;color identity;select .A:732 or .A:733 or .A:734 or .A:735 or .A:741 or .A:743 or .A:754 or .A:787 or .A:813 or .A:814 or .A:815 or .A:816 or .A:817 or .A:818 or .A:819 or .A:863 or .A:864 or .A:866 or .A:876 or .A:877 or .A:1036; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ILE732
4.275
ILE733
2.781
GLY734
3.483
GLU735
4.657
VAL741
4.513
LYS743
4.828
ALA754
3.157
VAL787
3.626
PHE813
4.104
GLU814
3.366
TYR815
2.459
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References | Top | ||||
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REF 1 | The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun. 2014 Mar 24;5:3505. | ||||
REF 2 | Structures of the CDK12/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding. Sci Rep. 2015 Nov 24;5:17122. | ||||
REF 3 | Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors. J Med Chem. 2018 Sep 13;61(17):7710-7728. | ||||
REF 4 | Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma. Eur J Med Chem. 2021 Oct 5;221:113481. | ||||
REF 5 | The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Sep;585(7824):293-297. | ||||
REF 6 | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84. | ||||
REF 7 | Structure-Based Design of Selective Noncovalent CDK12 Inhibitors. ChemMedChem. 2018 Feb 6;13(3):231-235. |
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