|
|
| Line 3: |
Line 3: |
| | <StructureSection load='4un0' size='340' side='right'caption='[[4un0]], [[Resolution|resolution]] 3.15Å' scene=''> | | <StructureSection load='4un0' size='340' side='right'caption='[[4un0]], [[Resolution|resolution]] 3.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4un0]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4cjy 4cjy]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UN0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UN0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4un0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4cjy 4cjy]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UN0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UN0 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4un0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4un0 OCA], [https://pdbe.org/4un0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4un0 RCSB], [https://www.ebi.ac.uk/pdbsum/4un0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4un0 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4un0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4un0 OCA], [http://pdbe.org/4un0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4un0 RCSB], [http://www.ebi.ac.uk/pdbsum/4un0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4un0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://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. | + | [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 == |
| - | [[http://www.uniprot.org/uniprot/CCNK_HUMAN CCNK_HUMAN]] May play a role in transcriptional regulation. In vitro, is associated with a kinase activity toward both RNA polymerase II C-terminal domain and CDK2 (CAK).<ref>PMID:10574912</ref> [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
Line 22: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Cyclin|Cyclin]] | + | *[[Cyclin 3D structures|Cyclin 3D structures]] |
| - | *[[Cyclin-dependent kinase|Cyclin-dependent kinase]] | + | *[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cyclin-dependent kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Bullock, A]] | + | [[Category: Bullock A]] |
| - | [[Category: Burgess-Brown, N]] | + | [[Category: Burgess-Brown N]] |
| - | [[Category: Carpenter, E P]] | + | [[Category: Carpenter EP]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Chaikuad A]] |
| - | [[Category: Clarke, S E.Dixon]] | + | [[Category: Dixon Clarke SE]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Edwards AM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Elkins JM]] |
| - | [[Category: Elkins, J M]] | + | [[Category: Goubin S]] |
| - | [[Category: Goubin, S]] | + | [[Category: Knapp S]] |
| - | [[Category: Knapp, S]] | + | [[Category: Kopec J]] |
| - | [[Category: Kopec, J]] | + | [[Category: Krojer T]] |
| - | [[Category: Krojer, T]] | + | [[Category: Mahajan RP]] |
| - | [[Category: Mahajan, R P]] | + | [[Category: Nowak R]] |
| - | [[Category: Nowak, R]] | + | [[Category: Pike ACW]] |
| - | [[Category: Pike, A C.W]] | + | [[Category: Sorrell FJ]] |
| - | [[Category: Sorrell, F J]] | + | [[Category: Williams E]] |
| - | [[Category: Williams, E]] | + | [[Category: Von Delft F]] |
| - | [[Category: Transferase]] | + | |
| Structural highlights
Disease
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
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.[1] [2] [3]
Publication Abstract from PubMed
Cyclin-dependent kinase 12 (CDK12) promotes transcriptional elongation by phosphorylation of the RNA polymerase II C-terminal domain (CTD). Structure-function studies show that this activity is dependent on a C-terminal kinase extension, as well as the binding of cyclin K (CycK). To better define these interactions we determined the crystal structure of the human CDK12/CycK complex with and without the kinase extension in the presence of AMP-PNP. The structures revealed novel features for a CDK, including a large beta4-beta5 loop insertion that contributes to the N-lobe interaction with the cyclin. We also observed two different conformations of the C-terminal kinase extension that effectively open and close the ATP pocket. Most notably, bound AMP-PNP was only observed when trapped in the closed state. Truncation of this C-terminal structure also diminished AMP-PNP binding, as well as the catalytic activity of the CDK12/CycK complex. Further kinetic measurements showed that the full length CDK12/CycK complex was significantly more active than the two crystallised constructs suggesting a critical role for additional domains. Overall, these results demonstrate the intrinsic flexibility of the C-terminal extension in CDK12 and highlight its importance for both ATP binding and kinase activity.
Structures of the CDK12/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding.,Dixon-Clarke SE, Elkins JM, Cheng SW, Morin GB, Bullock AN Sci Rep. 2015 Nov 24;5:17122. doi: 10.1038/srep17122. PMID:26597175[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ko TK, Kelly E, Pines J. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci. 2001 Jul;114(Pt 14):2591-603. PMID:11683387
- ↑ Iorns E, Martens-de Kemp SR, Lord CJ, Ashworth A. CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis. 2009 Oct;30(10):1696-701. doi: 10.1093/carcin/bgp187. Epub 2009, Aug 3. PMID:19651820 doi:http://dx.doi.org/10.1093/carcin/bgp187
- ↑ Bartkowiak B, Liu P, Phatnani HP, Fuda NJ, Cooper JJ, Price DH, Adelman K, Lis JT, Greenleaf AL. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010 Oct 15;24(20):2303-16. doi: 10.1101/gad.1968210. PMID:20952539 doi:http://dx.doi.org/10.1101/gad.1968210
- ↑ Dixon-Clarke SE, Elkins JM, Cheng SW, Morin GB, Bullock AN. 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. doi: 10.1038/srep17122. PMID:26597175 doi:http://dx.doi.org/10.1038/srep17122
|
