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PDBsum entry 6eii
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PDB id:
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Transferase
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Title:
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The crystal structure of ck2alpha in complex with compound 18
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Structure:
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Casein kinase ii subunit alpha. Chain: a, b. Fragment: residues 2-329 and n-terminal extension gsmdiefdddadddgsgsgsgsgs. Synonym: ck ii alpha. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: csnk2a1, ck2a1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.94Å
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R-factor:
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0.209
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R-free:
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0.234
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Authors:
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P.Brear,C.De Fusco,J.Iegre,M.Yoshida,S.Mitchell,M.Rossmann,L.Carro, H.Sore,M.Hyvonen,D.Spring
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Key ref:
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J.Iegre
et al.
(2018).
Second-generation CK2α inhibitors targeting the αD pocket.
Chem Sci,
9,
3041-3049.
PubMed id:
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Date:
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19-Sep-17
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Release date:
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28-Feb-18
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PROCHECK
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Headers
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References
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P68400
(CSK21_HUMAN) -
Casein kinase II subunit alpha from Homo sapiens
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Seq:
Struc:
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391 a.a.
326 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Chem Sci
9:3041-3049
(2018)
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PubMed id:
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Second-generation CK2α inhibitors targeting the αD pocket.
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J.Iegre,
P.Brear,
C.De Fusco,
M.Yoshida,
S.L.Mitchell,
M.Rossmann,
L.Carro,
H.F.Sore,
M.Hyvönen,
D.R.Spring.
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ABSTRACT
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CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic
mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very
attractive strategy considering that the ATP binding site is highly conserved
among other kinases. We have previously utilised a pocket outside the active
site to develop a novel CK2 inhibitor, CAM4066. Whilst CAM4066
bound to this new pocket it was also interacting with the ATP site: herein, we
describe an example of a CK2α inhibitor that binds completely outside the
active site. This second generation αD-site binding inhibitor, compound
CAM4712 (IC50 = 7 μM, GI50 = 10.0 ± 3.6 μM), has
numerous advantages over the previously reported CAM4066, including a
reduction in the number of rotatable bonds, the absence of amide groups
susceptible to the action of proteases and improved cellular permeability.
Unlike with CAM4066, there was no need to facilitate cellular uptake by
making a prodrug. Moreover, CAM4712 displayed no drop off between its
ability to inhibit the kinase in vitro (IC50) and the ability
to inhibit cell proliferation (GI50).
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