View source for 5cu2


==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=''>
== 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>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=54G:2-HYDROXY-5-METHYLBENZOIC+ACID'>54G</scene>, <scene name='pdbligand=551:METHYL+3-[(3-{[(2-CHLOROBIPHENYL-4-YL)METHYL]AMINO}PROPYL)AMINO]-3-OXOPROPANOATE'>551</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cu2 OCA], [http://pdbe.org/5cu2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cu2 RCSB], [http://www.ebi.ac.uk/pdbsum/5cu2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cu2 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/CSK21_HUMAN 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.<ref>PMID:11239457</ref> <ref>PMID:11704824</ref> <ref>PMID:16193064</ref> <ref>PMID:19188443</ref>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:28495381</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5cu2" style="background-color:#fffaf0;"></div>

==See Also==
*[[Casein kinase|Casein kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Brear, P]]
[[Category: Fusco, C De]]
[[Category: Georgiou, K H]]
[[Category: Hyvonen, M]]
[[Category: Spring, D]]
[[Category: Ck2a]]
[[Category: Ck2alpha]]
[[Category: Fragment based drug discovery]]
[[Category: High concentration screening]]
[[Category: Selective atp competitive inhibitor]]
[[Category: Surface entrophy reduction]]
[[Category: Transferase]]