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PDBsum entry 3zh8
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PDB id:
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Transferase
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Title:
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A novel small molecule apkc inhibitor
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Structure:
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Protein kinasE C iota type. Chain: a, b, c. Fragment: kinase domain, residues 248-596. Synonym: pkc iota, atypical protein kinasE C-lambda/iota, prkc- lambda/iota, apkc-lambda/iota, npkc-iota. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: high five.
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Resolution:
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2.74Å
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R-factor:
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0.213
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R-free:
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0.257
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Authors:
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S.Kjaer,A.G.Purkiss,B.Kostelecky,P.P.Knowles,E.Soriano,J.Murray-Rust, N.Q.Mcdonald
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Key ref:
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S.Kjær
et al.
(2013).
Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isoenzymes.
Biochem J,
451,
329-342.
PubMed id:
DOI:
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Date:
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20-Dec-12
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Release date:
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27-Feb-13
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PROCHECK
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Headers
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References
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P41743
(KPCI_HUMAN) -
Protein kinase C iota type from Homo sapiens
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Seq:
Struc:
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596 a.a.
320 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.11.13
- protein kinase C.
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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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DOI no:
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Biochem J
451:329-342
(2013)
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PubMed id:
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Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isoenzymes.
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S.Kjær,
M.Linch,
A.Purkiss,
B.Kostelecky,
P.P.Knowles,
C.Rosse,
P.Riou,
C.Soudy,
S.Kaye,
B.Patel,
E.Soriano,
J.Murray-Rust,
C.Barton,
C.Dillon,
J.Roffey,
P.J.Parker,
N.Q.McDonald.
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ABSTRACT
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The aPKC [atypical PKC (protein kinase C)] isoforms ι and ζ play crucial roles
in the formation and maintenance of cell polarity and represent attractive
anti-oncogenic drug targets in Ras-dependent tumours. To date, few
isoform-specific chemical biology tools are available to inhibit aPKC catalytic
activity. In the present paper, we describe the identification and functional
characterization of potent and selective thieno[2,3-d]pyrimidine-based chemical
inhibitors of aPKCs. A crystal structure of human PKCι kinase domain bound to a
representative compound, CRT0066854, reveals the basis for potent and selective
chemical inhibition. Furthermore, CRT0066854 displaces a crucial Asn-Phe-Asp
motif that is part of the adenosine-binding pocket and engages an acidic patch
used by arginine-rich PKC substrates. We show that CRT0066854 inhibits the LLGL2
(lethal giant larvae 2) phosphorylation in cell lines and exhibits phenotypic
effects in a range of cell-based assays. We conclude that this compound can be
used as a chemical tool to modulate aPKC activity in vitro and in vivo and may
guide the search for further aPKC-selective inhibitors.
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