View source for 4cxa


==Crystal structure of the human CDK12-cyclin K complex bound to AMPPNP==
<StructureSection load='4cxa' size='340' side='right'caption='[[4cxa]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cxa]] 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=4CXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CXA FirstGlance]. <br>
</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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</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'>[https://proteopedia.org/fgij/fg.htm?mol=4cxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cxa OCA], [https://pdbe.org/4cxa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cxa RCSB], [https://www.ebi.ac.uk/pdbsum/4cxa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cxa ProSAT]</span></td></tr>
</table>
== 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 ==
[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 ==
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<ref>PMID:26597175</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cxa" 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/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith C]]
[[Category: Bountra C]]
[[Category: Bullock A]]
[[Category: Burgess-Brown N]]
[[Category: Carpenter EP]]
[[Category: Dixon Clarke SE]]
[[Category: Edwards AM]]
[[Category: Elkins JM]]
[[Category: Faust B]]
[[Category: Froese S]]
[[Category: Goubin S]]
[[Category: Kopec J]]
[[Category: Mackenzie A]]
[[Category: Mahajan RP]]
[[Category: Nowak R]]
[[Category: Pike ACW]]
[[Category: Tallant C]]
[[Category: Von Delft F]]