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PDBsum entry 4z9l
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Transferase/inhibitor
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PDB id
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4z9l
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References listed in PDB file
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Key reference
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Title
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The structure of jnk3 in complex with small molecule inhibitors: structural basis for potency and selectivity.
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Authors
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G.Scapin,
S.B.Patel,
J.Lisnock,
J.W.Becker,
P.V.Lograsso.
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Ref.
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Chem Biol, 2003,
10,
705-712.
[DOI no: ]
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PubMed id
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Abstract
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The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein
(MAP) kinase family and regulate signal transduction in response to
environmental stress. Activation of JNK3, a neuronal-specific isoform, has been
associated with neurological damage, and as such, JNK3 may represent an
attractive target for the treatment of neurological disorders. The MAP kinases
share between 50% and 80% sequence identity. In order to obtain efficacious and
safe compounds, it is necessary to address the issues of potency and
selectivity. We report here four crystal structures of JNK3 in complex with
three different classes of inhibitors. These structures provide a clear picture
of the interactions that each class of compound made with the kinase. Knowledge
of the atomic interactions involved in these diverse binding modes provides a
platform for structure-guided modification of these compounds, or the de novo
design of novel inhibitors that could satisfy the need for potency and
selectivity.
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Figure 1.
Figure 1. Schematic Representation of the ATP Binding Site
in KinasesATP (in ball-and-sticks) interacts mainly with the
linker/adenine binding region (1), the ribose binding region
(2), and the phosphate binding region (3). The two hydrophobic
regions I (4) and II (5) do not directly interact with ATP and
contain residues that vary among kinases, thus providing
possibilities for the development of selective inhibitors [17].
Figures 1, 2B, and 3–6 were made with RIBBONS [42].
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Figure 5.
Figure 5. Binding of Compound 3 to JNK3(A) Overlay of the
Cα traces of JNK3:compound 1 (magenta) and JNK3:compound 3
complexes (yellow) in the region of the glycine-rich loop
(G71-V78). The conformational change observed for residues
Ile70–Ile77 was ligand induced.(B) Close-up of the compound 3
binding site; hydrogen bond interactions with protein atoms are
shown as blue dotted lines.
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2003,
10,
705-712)
copyright 2003.
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Secondary reference #1
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Title
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Achieving high quality ligand chemistry in protein-Li crystal structures for drug design
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Authors
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O.S.Smart,
G.Bricogne.
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Ref.
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multifaceted roles of ...
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