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5cu2

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Revision as of 10:23, 1 April 2020

Crystal structure of CK2alpha with 2-hydroxy-5-methylbenzoic acid and (methyl 4-((3-(3-chloro-4-(phenyl)benzylamino)propyl)amino)-4-oxobutanoat bound

Structural highlights

5cu2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CSK21_HUMAN] Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Recently we reported the discovery of a potent and selective CK2alpha inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (alphaD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the alphaD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066.,De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvonen M, Spring DR Bioorg Med Chem. 2017 Apr 30. pii: S0968-0896(16)31479-1. doi:, 10.1016/j.bmc.2017.04.037. PMID:28495381^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H. A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell. 2001 Feb;7(2):283-92. PMID:11239457
↑ Sayed M, Pelech S, Wong C, Marotta A, Salh B. Protein kinase CK2 is involved in G2 arrest and apoptosis following spindle damage in epithelial cells. Oncogene. 2001 Oct 25;20(48):6994-7005. PMID:11704824 doi:10.1038/sj.onc.1204894
↑ Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K. Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J. 2005 Oct 19;24(20):3532-42. Epub 2005 Sep 29. PMID:16193064 doi:10.1038/sj.emboj.7600827
↑ St-Denis NA, Derksen DR, Litchfield DW. Evidence for regulation of mitotic progression through temporal phosphorylation and dephosphorylation of CK2alpha. Mol Cell Biol. 2009 Apr;29(8):2068-81. doi: 10.1128/MCB.01563-08. Epub 2009 Feb, 2. PMID:19188443 doi:10.1128/MCB.01563-08
↑ De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvonen M, Spring DR. A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066. Bioorg Med Chem. 2017 Apr 30. pii: S0968-0896(16)31479-1. doi:, 10.1016/j.bmc.2017.04.037. PMID:28495381 doi:http://dx.doi.org/10.1016/j.bmc.2017.04.037

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5cu2"

@@ Line 1: / Line 1: @@
 ==Crystal structure of CK2alpha with 2-hydroxy-5-methylbenzoic acid and (methyl 4-((3-(3-chloro-4-(phenyl)benzylamino)propyl)amino)-4-oxobutanoat bound==
-<StructureSection load='5cu2' size='340' side='right' caption='[[5cu2]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
+<StructureSection load='5cu2' size='340' side='right'caption='[[5cu2]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5cu2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CU2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CU2 FirstGlance]. <br>
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5cu2" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Casein kinase 3D structures|Casein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Brear, P]]

5cu2

From Proteopedia

Revision as of 10:23, 1 April 2020

Crystal structure of CK2alpha with 2-hydroxy-5-methylbenzoic acid and (methyl 4-((3-(3-chloro-4-(phenyl)benzylamino)propyl)amino)-4-oxobutanoat bound

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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