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7x4h

From Proteopedia

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Current revision

Crystal structure of CK2a1 complexed with AG1112

Structural highlights

7x4h is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.77Å
Ligands:
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

Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2alpha1 and/or CK2alpha2) and two regulatory subunits (CK2beta). CK2alpha1 is a drug target for nephritis and cancers, while CK2alpha2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2alpha1 and CK2alpha2 make it difficult to design CK2alpha1-specific inhibitors. Herein, the crystal structures of CK2alpha1 and CK2alpha2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein-inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2alpha1, but not to CK2alpha2, at the CK2beta protein-protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2alpha1 inhibitors.

Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2alpha1-selective inhibitors.,Ikeda A, Tsuyuguchi M, Kitagawa D, Sawa M, Nakamura S, Nakanishi I, Kinoshita T Biochem Biophys Res Commun. 2022 Nov 19;630:30-35. doi: , 10.1016/j.bbrc.2022.09.040. Epub 2022 Sep 15. PMID:36130444^[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
↑ Ikeda A, Tsuyuguchi M, Kitagawa D, Sawa M, Nakamura S, Nakanishi I, Kinoshita T. Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2alpha1-selective inhibitors. Biochem Biophys Res Commun. 2022 Nov 19;630:30-35. doi: , 10.1016/j.bbrc.2022.09.040. Epub 2022 Sep 15. PMID:36130444 doi:http://dx.doi.org/10.1016/j.bbrc.2022.09.040

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7x4h"

Categories: Homo sapiens | Large Structures | Ikeda A | Kinoshita T | Tsuyuguchi M

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7x4h]] is a 1 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=7X4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7X4H FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8BH:5-azanyl-3-[(~{Z})-1-cyano-2-(1~{H}-indol-3-yl)ethenyl]-1~{H}-pyrazole-4-carbonitrile'>8BH</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]] 1.77&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8BH:5-azanyl-3-[(~{Z})-1-cyano-2-(1~{H}-indol-3-yl)ethenyl]-1~{H}-pyrazole-4-carbonitrile'>8BH</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=7x4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7x4h OCA], [https://pdbe.org/7x4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7x4h RCSB], [https://www.ebi.ac.uk/pdbsum/7x4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7x4h ProSAT]</span></td></tr>
 </table>

7x4h

From Proteopedia

Current revision

Crystal structure of CK2a1 complexed with AG1112

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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