4un0

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'''Unreleased structure'''
 
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The entry 4un0 is ON HOLD
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==Crystal structure of the human CDK12-cyclinK complex==
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<StructureSection load='4un0' size='340' side='right'caption='[[4un0]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
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== Structural highlights ==
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<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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15&#8491;</td></tr>
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<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>
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<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>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors: Dixon Clarke, S.E., Elkins, J.M., Pike, A.C.W., Chaikuad, A., Goubin, S., Krojer, T., Sorrell, F.J., Nowak, R., Williams, E., Kopec, J., Mahajan, R.P., Burgess-Brown, N., Carpenter, E.P., Knapp, S., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Bullock, A.
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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<ref>PMID:26597175</ref>
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Description: Crystal structure of the human CDK12-cyclinK complex
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4un0" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Cyclin 3D structures|Cyclin 3D structures]]
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*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Arrowsmith CH]]
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[[Category: Bountra C]]
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[[Category: Bullock A]]
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[[Category: Burgess-Brown N]]
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[[Category: Carpenter EP]]
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[[Category: Chaikuad A]]
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[[Category: Dixon Clarke SE]]
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[[Category: Edwards AM]]
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[[Category: Elkins JM]]
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[[Category: Goubin S]]
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[[Category: Knapp S]]
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[[Category: Kopec J]]
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[[Category: Krojer T]]
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[[Category: Mahajan RP]]
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[[Category: Nowak R]]
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[[Category: Pike ACW]]
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[[Category: Sorrell FJ]]
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[[Category: Williams E]]
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[[Category: Von Delft F]]

Current revision

Crystal structure of the human CDK12-cyclinK complex

PDB ID 4un0

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