4un0

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the human CDK12-cyclinK complex

Structural highlights

4un0 is a 4 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 4cjy. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.15Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4un0"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the human CDK12-cyclinK complex==
-<StructureSection load='4un0' size='340' side='right' caption='[[4un0]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
+<StructureSection load='4un0' size='340' side='right'caption='[[4un0]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4un0]] is a 4 chain structure. 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><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='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><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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-<tr><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://www.rcsb.org/pdb/explore.do?structureId=4un0 RCSB], [http://www.ebi.ac.uk/pdbsum/4un0 PDBsum]</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>
-<table>
+</table>
 == 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 ==
-[[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;">
+== 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 4un0" 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: Cyclin-dependent kinase]]
+[[Category: Homo sapiens]]
-[[Category: Arrowsmith, C H.]]
+[[Category: Large Structures]]
-[[Category: Bountra, C.]]
+[[Category: Arrowsmith CH]]
-[[Category: Bullock, A.]]
+[[Category: Bountra C]]
-[[Category: Burgess-Brown, N.]]
+[[Category: Bullock A]]
-[[Category: Carpenter, E P.]]
+[[Category: Burgess-Brown N]]
-[[Category: Chaikuad, A.]]
+[[Category: Carpenter EP]]
-[[Category: Clarke, S E.Dixon.]]
+[[Category: Chaikuad A]]
-[[Category: Delft, F von.]]
+[[Category: Dixon Clarke SE]]
-[[Category: Edwards, A M.]]
+[[Category: Edwards AM]]
-[[Category: Elkins, J M.]]
+[[Category: Elkins JM]]
-[[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, R P.]]
+[[Category: Mahajan RP]]
-[[Category: Nowak, R.]]
+[[Category: Nowak R]]
-[[Category: Pike, A C.W.]]
+[[Category: Pike ACW]]
-[[Category: Sorrell, F J.]]
+[[Category: Sorrell FJ]]
-[[Category: Williams, E.]]
+[[Category: Williams E]]
-[[Category: Transferase]]
+[[Category: Von Delft F]]

4un0

From Proteopedia

Current revision

Crystal structure of the human CDK12-cyclinK complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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