3at2: Difference between revisions
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==Crystal structure of CK2alpha== | |||
<StructureSection load='3at2' size='340' side='right'caption='[[3at2]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3at2]] 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=3AT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AT2 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]] 1.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=3at2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3at2 OCA], [https://pdbe.org/3at2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3at2 RCSB], [https://www.ebi.ac.uk/pdbsum/3at2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3at2 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 == | |||
The detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit alpha (CK2alpha), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2alpha, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2alpha, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2alpha. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2alpha inhibitors. | |||
A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase.,Kinoshita T, Sekiguchi Y, Fukada H, Nakaniwa T, Tada T, Nakamura S, Kitaura K, Ohno H, Suzuki Y, Hirasawa A, Nakanishi I, Tsujimoto G Mol Cell Biochem. 2011 Oct;356(1-2):97-105. Epub 2011 Jul 7. PMID:21735094<ref>PMID:21735094</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3at2" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Casein kinase|Casein kinase]] | *[[Casein kinase 3D structures|Casein kinase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Kinoshita | [[Category: Kinoshita T]] | ||
Latest revision as of 18:54, 4 October 2023
Crystal structure of CK2alphaCrystal structure of CK2alpha
Structural highlights
FunctionCSK21_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 PubMedThe detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit alpha (CK2alpha), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2alpha, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2alpha, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2alpha. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2alpha inhibitors. A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase.,Kinoshita T, Sekiguchi Y, Fukada H, Nakaniwa T, Tada T, Nakamura S, Kitaura K, Ohno H, Suzuki Y, Hirasawa A, Nakanishi I, Tsujimoto G Mol Cell Biochem. 2011 Oct;356(1-2):97-105. Epub 2011 Jul 7. PMID:21735094[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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