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PDBsum entry 1kv2
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Inhibition of p38 map kinase by utilizing a novel allosteric binding site.
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Authors
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C.Pargellis,
L.Tong,
L.Churchill,
P.F.Cirillo,
T.Gilmore,
A.G.Graham,
P.M.Grob,
E.R.Hickey,
N.Moss,
S.Pav,
J.Regan.
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Ref.
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Nat Struct Biol, 2002,
9,
268-272.
[DOI no: ]
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PubMed id
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Abstract
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The p38 MAP kinase plays a crucial role in regulating the production of
proinflammatory cytokines, such as tumor necrosis factor and interleukin-1.
Blocking this kinase may offer an effective therapy for treating many
inflammatory diseases. Here we report a new allosteric binding site for a diaryl
urea class of highly potent and selective inhibitors against human p38 MAP
kinase. The formation of this binding site requires a large conformational
change not observed previously for any of the protein Ser/Thr kinases. This
change is in the highly conserved Asp-Phe-Gly motif within the active site of
the kinase. Solution studies demonstrate that this class of compounds has slow
binding kinetics, consistent with the requirement for conformational change.
Improving interactions in this allosteric pocket, as well as establishing
binding interactions in the ATP pocket, enhanced the affinity of the inhibitors
by 12,000-fold. One of the most potent compounds in this series, BIRB 796, has
picomolar affinity for the kinase and low nanomolar inhibitory activity in cell
culture.
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Figure 2.
Figure 2. A new allosteric binding pocket for compound 1 in
human p38 MAP kinase. a, Schematic drawing of the structure
of p38 MAP kinase in complex with compound 1. The inhibitor is
shown as a stick model, with carbon atoms in green. The expected
location of the ATP molecule^8 (purple for carbon atoms) is
shown for reference. b, Final 2F[o] - F[c] electron density map
for compound 1, contoured at 1  level.
Panel (a) is produced with RIBBONS27 and panel (b) with SETOR28.
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Figure 3.
Figure 3. A conformational change in the kinase is required for
the binding of diaryl urea inhibitors. a, Stereo view showing
the conformational change for the DFG motif. The DFG-in
conformation is shown with the carbon atoms in light blue, and
the DFG-out conformation is in gray. Also shown is the overlay
of the binding modes of compound 1 (green), the 3'-iodo analog
of SB 203580 (cyan)8 and ATP (purple). b, Molecular surface of
the p38 MAP kinase in the active site region in complex with
compound 1. For clarity, residues in the DFG motif are shown as
a stick model. The ATP molecule is shown for reference. c,
Stereo view showing the binding pocket (gray for carbon atoms)
for BIRB 796 (green). Also shown is compound 1 and the
conformation of Glu 71 (cyan) in that complex. Produced with
GRASP29.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
268-272)
copyright 2002.
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