Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| 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 | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Phosphonothreonine | Ligand Info | |||
| Canonical SMILES | CC(C(C(=O)O)N)OP(=O)(O)O | ||||
| InChI | 1S/C4H10NO6P/c1-2(3(5)4(6)7)11-12(8,9)10/h2-3H,5H2,1H3,(H,6,7)(H2,8,9,10)/t2-,3+/m1/s1 | ||||
| InChIKey | USRGIUJOYOXOQJ-GBXIJSLDSA-N | ||||
| PubChem Compound ID | 3246323 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 4NST Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | ||||||
| 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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| PDB ID: 6CKX 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 | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [2] |
| 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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| PDB ID: 7NXK Crystal structure of human Cdk12/Cyclin K in complex with the inhibitor BSJ-01-175 | ||||||
| Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [3] |
| 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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| PDB ID: 6TD3 Structure of DDB1 bound to CR8-engaged CDK12-cyclinK | ||||||
| Method | X-ray diffraction | Resolution | 3.46 Å | Mutation | Yes | [4] |
| 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 .TPO or .TPO2 or .TPO3 or :3TPO;style chemicals stick;color identity;select .B:773 or .B:858 or .B:880 or .B:882 or .B:891 or .B:892 or .B:894 or .B:895 or .B:896 or .B:906 or .B:911 or .B:913; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 5ACB Crystal Structure of the Human Cdk12-Cyclink Complex | ||||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [5] |
| 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 .TPO or .TPO2 or .TPO3 or :3TPO;style chemicals stick;color identity;select .C:858 or .C:882 or .C:891 or .C:892 or .C:894 or .C:895 or .C:896 or .C:911 or .C:913; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 4CXA Crystal structure of the human CDK12-cyclin K complex bound to AMPPNP | ||||||
| Method | X-ray diffraction | Resolution | 3.15 Å | Mutation | No | [6] |
| 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 .TPO or .TPO2 or .TPO3 or :3TPO;style chemicals stick;color identity;select .A:773 or .A:858 or .A:880 or .A:882 or .A:891 or .A:892 or .A:894 or .A:895 or .A:896 or .A:913; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6B3E Crystal structure of human CDK12/CyclinK in complex with an inhibitor | ||||||
| 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 .TPO or .TPO2 or .TPO3 or :3TPO;style chemicals stick;color identity;select .A:858 or .A:882 or .A:891 or .A:892 or .A:894 or .A:895 or .A:896 or .A:913; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun. 2014 Mar 24;5:3505. | ||||
| REF 2 | 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 3 | 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 4 | The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020 Sep;585(7824):293-297. | ||||
| REF 5 | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84. | ||||
| REF 6 | 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 7 | Structure-Based Design of Selective Noncovalent CDK12 Inhibitors. ChemMedChem. 2018 Feb 6;13(3):231-235. | ||||
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