9qy7

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of 54e bound to CK2a

Structural highlights

9qy7 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 1.39Å
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 2alpha (CK2alpha) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2alpha has a unique cryptic binding site, the alphaD pocket, that offers the potential for inhibitors with improved kinase selectivity. The prototype bivalent molecule CAM4066 (6) confirmed that improved selectivity could be achieved while binding in both the ATP-binding site and the alphaD pocket. A drug discovery project to develop a new series of bivalent CK2alpha inhibitors with increased cell potency and selectivity identified 61f (APL-5125), a highly potent, ATP-competitive CK2alpha inhibitor with exquisite kinase selectivity and cellular potency. Compound 61f demonstrates in vivo inhibition of p-AKT S129 in tumors (HCT116) following once-daily oral administration and shows a clear PK-PD relationship with unbound drug exposure. 61f has a superior preclinical profile to existing CK2alpha inhibitors and is currently under evaluation in patients with advanced solid tumors.

Exploiting the Cryptic alphaD Pocket of Casein Kinase 2alpha (CK2alpha) to Deliver Highly Potent and Selective Type 1 Inhibitors.,Glossop PA, Brear P, Wright S, Flanagan N, Glossop MS, Lane CAL, Butt RP, Spring DR, Hyvonen M, Cawkill D J Med Chem. 2025 Oct 14. doi: 10.1021/acs.jmedchem.5c01807. PMID:41085029^[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
↑ Glossop PA, Brear P, Wright S, Flanagan N, Glossop MS, Lane CAL, Butt RP, Spring DR, Hyvönen M, Cawkill D. Exploiting the Cryptic αD Pocket of Casein Kinase 2α (CK2α) to Deliver Highly Potent and Selective Type 1 Inhibitors. J Med Chem. 2025 Oct 14. PMID:41085029 doi:10.1021/acs.jmedchem.5c01807

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/9qy7"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9qy7 is ON HOLD  until Paper Publication
+==Crystal Structure of 54e bound to CK2a==
+<StructureSection load='9qy7' size='340' side='right'caption='[[9qy7]], [[Resolution|resolution]] 1.39&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9qy7]] 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=9QY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9QY7 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.39&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JB4:5-[2-[4-[[3-chloranyl-4-(trifluoromethyloxy)phenyl]methylamino]butoxy]ethylamino]benzo[c][2,6]naphthyridine-8-carboxamide'>A1JB4</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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=9qy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9qy7 OCA], [https://pdbe.org/9qy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9qy7 RCSB], [https://www.ebi.ac.uk/pdbsum/9qy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9qy7 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://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 ==
+Casein kinase 2alpha (CK2alpha) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2alpha has a unique cryptic binding site, the alphaD pocket, that offers the potential for inhibitors with improved kinase selectivity. The prototype bivalent molecule CAM4066 (6) confirmed that improved selectivity could be achieved while binding in both the ATP-binding site and the alphaD pocket. A drug discovery project to develop a new series of bivalent CK2alpha inhibitors with increased cell potency and selectivity identified 61f (APL-5125), a highly potent, ATP-competitive CK2alpha inhibitor with exquisite kinase selectivity and cellular potency. Compound 61f demonstrates in vivo inhibition of p-AKT S129 in tumors (HCT116) following once-daily oral administration and shows a clear PK-PD relationship with unbound drug exposure. 61f has a superior preclinical profile to existing CK2alpha inhibitors and is currently under evaluation in patients with advanced solid tumors.
-Authors: Brear, P., Glossop, P., Pandey, S., Hyvonen, M., Spring, D., Butt, R., Cawkill, D.
+Exploiting the Cryptic alphaD Pocket of Casein Kinase 2alpha (CK2alpha) to Deliver Highly Potent and Selective Type 1 Inhibitors.,Glossop PA, Brear P, Wright S, Flanagan N, Glossop MS, Lane CAL, Butt RP, Spring DR, Hyvonen M, Cawkill D J Med Chem. 2025 Oct 14. doi: 10.1021/acs.jmedchem.5c01807. PMID:41085029<ref>PMID:41085029</ref>
-Description: Crystal Structure of 54e bound to CK2a
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Glossop, P]]
+<div class="pdbe-citations 9qy7" style="background-color:#fffaf0;"></div>
-[[Category: Hyvonen, M]]
+== References ==
-[[Category: Pandey, S]]
+<references/>
-[[Category: Cawkill, D]]
+__TOC__
-[[Category: Butt, R]]
+</StructureSection>
-[[Category: Spring, D]]
+[[Category: Homo sapiens]]
-[[Category: Brear, P]]
+[[Category: Large Structures]]
+[[Category: Brear P]]
+[[Category: Butt R]]
+[[Category: Cawkill D]]
+[[Category: Glossop P]]
+[[Category: Hyvonen M]]
+[[Category: Pandey S]]
+[[Category: Spring D]]

9qy7

From Proteopedia

Current revision

Crystal Structure of 54e bound to CK2a

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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