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PDBsum entry 3fzs
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References listed in PDB file
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Key reference
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Title
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Structural characterization of proline-Rich tyrosine kinase 2 (pyk2) reveals a unique (dfg-Out) conformation and enables inhibitor design.
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Authors
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S.Han,
A.Mistry,
J.S.Chang,
D.Cunningham,
M.Griffor,
P.C.Bonnette,
H.Wang,
B.A.Chrunyk,
G.E.Aspnes,
D.P.Walker,
A.D.Brosius,
L.Buckbinder.
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Ref.
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J Biol Chem, 2009,
284,
13193-13201.
[DOI no: ]
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PubMed id
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Abstract
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Proline-rich tyrosine kinase 2 (PYK2) is a cytoplasmic, non-receptor tyrosine
kinase implicated in multiple signaling pathways. It is a negative regulator of
osteogenesis and considered a viable drug target for osteoporosis treatment. The
high-resolution structures of the human PYK2 kinase domain with different
inhibitor complexes establish the conventional bilobal kinase architecture and
show the conformational variability of the DFG loop. The basis for the lack of
selectivity for the classical kinase inhibitor, PF-431396, within the FAK family
is explained by our structural analyses. Importantly, the novel DFG-out
conformation with two diarylurea inhibitors (BIRB796, PF-4618433) reveals a
distinct subclass of non-receptor tyrosine kinases identifiable by the
gatekeeper Met-502 and the unique hinge loop conformation of Leu-504. This is
the first example of a leucine residue in the hinge loop that blocks the ATP
binding site in the DFG-out conformation. Our structural, biophysical, and
pharmacological studies suggest that the unique features of the DFG motif,
including Leu-504 hinge-loop variability, can be exploited for the development
of selective protein kinase inhibitors.
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Figure 2.
A, molecular surface of the PYK2 in the active site region in
complex with ATPγS (magenta). Critical side chains are labeled
(ball and stick representation) with hydrogen bonds (dashed
lines). B, active site of PYK2 bound to PF-431396 (magenta).
Hydrophobic residues interacting with the sulfonamide group are
shown in yellow.
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Figure 6.
DFG-out conformation in PYK2. A, conformational change for
the DFG motif upon binding of BIRB796. DFG-in motif in Apo
structure is shown in purple and the DFG-out conformation in
green. B, superposition of the structures of the PYK2: BIRB796
complex (green) from p38: BIRB796 complex (orange) showing
significant differences represented by arrows. C, stereoview
showing the DFG-out binding sites of Imatinib from Abl (yellow),
Sorafenib from B-RAF (gray), and BIRB796 from PYK2 (cyan) with
corresponding gatekeeper residues. D, β-turn conformation in
the hinge region with hydrogen bonds in dashes; Apo structure
(pink), PYK2:BIRB796 complex (cyan), and PYK2:PF-4618433 (green).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
13193-13201)
copyright 2009.
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