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PDBsum entry 4bky
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PDB id:
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Transferase
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Title:
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Crystal structure of unphosphorylated maternal embryonic leucine zipper kinase (melk) in complex with pyrrolopyrazole inhibitor
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Structure:
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Maternal embryonic leucine zipper kinase. Chain: a. Fragment: kinase and uba domains, residues 2-340. Synonym: hmelk, protein kinase eg3, peg3 kinase, protein kinase pk38, hpk38, tyrosine-protein kinase melk. Engineered: 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: sf21.
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Resolution:
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1.83Å
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R-factor:
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0.204
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R-free:
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0.223
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Authors:
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G.Canevari,S.Re Depaolini,U.Cucchi,B.Forte,P.Carpinelli,J.A.Bertrand
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Key ref:
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G.Canevari
et al.
(2013).
Structural insight into maternal embryonic leucine zipper kinase (MELK) conformation and inhibition toward structure-based drug design.
Biochemistry,
52,
6380-6387.
PubMed id:
DOI:
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Date:
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30-Apr-13
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Release date:
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21-Aug-13
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PROCHECK
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Headers
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References
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Q14680
(MELK_HUMAN) -
Maternal embryonic leucine zipper kinase from Homo sapiens
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Seq:
Struc:
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651 a.a.
311 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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Enzyme class 2:
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E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Enzyme class 3:
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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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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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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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Biochemistry
52:6380-6387
(2013)
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PubMed id:
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Structural insight into maternal embryonic leucine zipper kinase (MELK) conformation and inhibition toward structure-based drug design.
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G.Canevari,
S.Re Depaolini,
U.Cucchi,
J.A.Bertrand,
E.Casale,
C.Perrera,
B.Forte,
P.Carpinelli,
E.R.Felder.
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ABSTRACT
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Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types
of tumor, including breast, prostate, and brain tumors. Its expression is
generally associated with cell survival, cell proliferation, and resistance to
apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is
recently attracting considerable interest. Here we report the first structures
of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed
light on the role of the MELK UBA domain, provide a characterization of the
kinase active site, and identify key residues for achieving high potency, laying
the groundwork for structure-based drug design efforts.
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Links
