5acb

From Proteopedia

(Difference between revisions)

Revision as of 07:22, 3 July 2019

Crystal Structure of the Human Cdk12-Cyclink Complex

Structural highlights

5acb is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Activity:	Cyclin-dependent kinase, with EC number 2.7.11.22
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 kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.,Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke SE, Abraham BJ, Greifenberg AK, Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manz T, Hao M, Bartkowiak B, Greenleaf AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS Nat Chem Biol. 2016 Oct;12(10):876-884. doi: 10.1038/nchembio.2166. Epub 2016 Aug, 29. PMID:27571479^[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
↑ Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke SE, Abraham BJ, Greifenberg AK, Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manz T, Hao M, Bartkowiak B, Greenleaf AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-884. doi: 10.1038/nchembio.2166. Epub 2016 Aug, 29. PMID:27571479 doi:http://dx.doi.org/10.1038/nchembio.2166

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/5acb"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the Human Cdk12-Cyclink Complex==
-<StructureSection load='5acb' size='340' side='right' caption='[[5acb]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='5acb' size='340' side='right'caption='[[5acb]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5acb]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ACB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ACB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5acb]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ACB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ACB FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5I1:N-[4-[(3R)-3-[[5-CHLORANYL-4-(1H-INDOL-3-YL)PYRIMIDIN-2-YL]AMINO]PIPERIDIN-1-YL]CARBONYLPHENYL]-4-(DIMETHYLAMINO)BUTANAMIDE'>5I1</scene></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>
@@ Line 22: / Line 22: @@
 </div>
 <div class="pdbe-citations 5acb" 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/>
@@ Line 27: / Line 31: @@
 </StructureSection>
 [[Category: Cyclin-dependent kinase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arrowsmith, C H]]
 [[Category: Bountra, C]]

5acb

From Proteopedia

Revision as of 07:22, 3 July 2019

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?)

Views

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