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PDBsum entry 4mf0
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Transferase/transferase inhibitor
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PDB id
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4mf0
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Itk kinase domain in complex with benzothiazole inhibitor compound 12a (1s,2s)-2-{4-[(dimethylamino)methyl]phenyl}-n-[6-(pyridin-3-yl)-1,3- benzothiazol-2-yl]cyclopropanecarboxamide (12a)
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Structure:
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Tyrosine-protein kinase itk/tsk. Chain: a, b. Fragment: unp residues 357-620. Synonym: interleukin-2-inducible t-cell kinase, il-2-inducible t-cell kinase, kinase emt, t-cell-specific kinase, tyrosine-protein kinase lyk. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: emt, itk, lyk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.67Å
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R-factor:
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0.215
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R-free:
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0.268
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Authors:
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C.Eigenbrot,S.Shia
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Key ref:
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C.H.MacKinnon
et al.
(2013).
Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).
Bioorg Med Chem Lett,
23,
6331-6335.
PubMed id:
DOI:
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Date:
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27-Aug-13
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Release date:
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13-Nov-13
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PROCHECK
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Headers
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References
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Q08881
(ITK_HUMAN) -
Tyrosine-protein kinase ITK/TSK from Homo sapiens
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Seq:
Struc:
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620 a.a.
240 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:
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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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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
23:6331-6335
(2013)
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PubMed id:
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Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).
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C.H.MacKinnon,
K.Lau,
J.D.Burch,
Y.Chen,
J.Dines,
X.Ding,
C.Eigenbrot,
A.Heifetz,
A.Jaochico,
A.Johnson,
J.Kraemer,
S.Kruger,
T.M.Krülle,
M.Liimatta,
J.Ly,
R.Maghames,
C.A.Montalbetti,
D.F.Ortwine,
Y.Pérez-Fuertes,
S.Shia,
D.B.Stein,
G.Trani,
D.G.Vaidya,
X.Wang,
S.M.Bromidge,
L.C.Wu,
Z.Pei.
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ABSTRACT
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Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell
receptor signalling cascade, may represent a novel treatment for allergic
asthma. Here we report the structure-based optimization of a series of
benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against
ITK with good cellular activity and kinase selectivity. We also elucidate the
binding mode of these inhibitors by solving the X-ray crystal structures of
several inhibitor-ITK complexes.
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Links
