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==Crystal structure of human CDK12/CyclinK in complex with an inhibitor== | ==Crystal structure of human CDK12/CyclinK in complex with an inhibitor== | ||
<StructureSection load='6b3e' size='340' side='right' caption='[[6b3e]], [[Resolution|resolution]] 3.06Å' scene=''> | <StructureSection load='6b3e' size='340' side='right'caption='[[6b3e]], [[Resolution|resolution]] 3.06Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6b3e]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B3E OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6b3e]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B3E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B3E FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CJM: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'>CJM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.06Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJM: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'>CJM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6b3e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3e OCA], [https://pdbe.org/6b3e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b3e RCSB], [https://www.ebi.ac.uk/pdbsum/6b3e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/CDK12_HUMAN CDK12_HUMAN] Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2. | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/CDK12_HUMAN CDK12_HUMAN] Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors.<ref>PMID:11683387</ref> <ref>PMID:19651820</ref> <ref>PMID:20952539</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
CDK12 knockdown via siRNA reduces transcription of DNA damage response genes and sensitizes BRCA wild type cells to PARP inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5. Further structure guided optimization delivered a series of selective CDK12 inhibitors, including compound 7. Profiling of this compound across CDK9, 7, 2 and 1 at high ATP concentration, single point kinase panel screening against 352 targets at 0.1 microM, and proteomics via kinase affinity matrix technology demonstrated selectivity. This series of compounds inhibit phosphorylation of Ser2 on the C-terminal repeat domain of RNA pol II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells. | |||
Structure Based Design of Selective Non-covalent CDK12 Inhibitors.,Johannes J, Denz CR, Su N, Wu A, Impastato AC, Mlynarski S, Varnes JG, Prince DB, Cidado J, Gao N, Haddrick M, Jones NH, Li S, Li X, Liu Y, Nguyen TB, O'Connell N, Rivers E, Robbins DW, Tomlinson R, Yao T, Ferguson AD, Lamb ML, Manchester JI, Guichard S ChemMedChem. 2017 Dec 20. doi: 10.1002/cmdc.201700695. PMID:29266803<ref>PMID:29266803</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6b3e" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclin 3D structures|Cyclin 3D structures]] | |||
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Ferguson AD]] | ||
Latest revision as of 17:32, 4 October 2023
Crystal structure of human CDK12/CyclinK in complex with an inhibitorCrystal structure of human CDK12/CyclinK in complex with an inhibitor
Structural highlights
DiseaseCDK12_HUMAN Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2. FunctionCDK12_HUMAN Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors.[1] [2] [3] Publication Abstract from PubMedCDK12 knockdown via siRNA reduces transcription of DNA damage response genes and sensitizes BRCA wild type cells to PARP inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5. Further structure guided optimization delivered a series of selective CDK12 inhibitors, including compound 7. Profiling of this compound across CDK9, 7, 2 and 1 at high ATP concentration, single point kinase panel screening against 352 targets at 0.1 microM, and proteomics via kinase affinity matrix technology demonstrated selectivity. This series of compounds inhibit phosphorylation of Ser2 on the C-terminal repeat domain of RNA pol II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells. Structure Based Design of Selective Non-covalent CDK12 Inhibitors.,Johannes J, Denz CR, Su N, Wu A, Impastato AC, Mlynarski S, Varnes JG, Prince DB, Cidado J, Gao N, Haddrick M, Jones NH, Li S, Li X, Liu Y, Nguyen TB, O'Connell N, Rivers E, Robbins DW, Tomlinson R, Yao T, Ferguson AD, Lamb ML, Manchester JI, Guichard S ChemMedChem. 2017 Dec 20. doi: 10.1002/cmdc.201700695. PMID:29266803[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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