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PDBsum entry 3fqs
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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 insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.
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Authors
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A.G.Villaseñor,
R.Kondru,
H.Ho,
S.Wang,
E.Papp,
D.Shaw,
J.W.Barnett,
M.F.Browner,
A.Kuglstatter.
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Ref.
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Chem Biol Drug Des, 2009,
73,
466-470.
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PubMed id
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Abstract
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Spleen tyrosine kinase is considered an attractive drug target for the treatment
of allergic and antibody mediated autoimmune diseases. We have determined the
co-crystal structures of spleen tyrosine kinase complexed with three known
inhibitors: YM193306, a 7-azaindole derivative and R406. The
cis-cyclohexyldiamino moiety of YM193306 is forming four hydrophobically
shielded polar interactions with the spleen tyrosine kinase protein and is
therefore crucial for the high potency of this inhibitor. Its primary amino
group is inducing a conformational change of the spleen tyrosine kinase DFG Asp
side chain. The crystal structure of the 7-azaindole derivative bound to spleen
tyrosine kinase is the first demonstration of a 2-substituted 7-azaindole bound
to a protein kinase. Its indole-amide substituent is tightly packed between the
N- and C-terminal kinase lobes. The co-crystal structure of the spleen tyrosine
kinase-R406 complex shows two main differences to the previously reported
structure of spleen tyrosine kinase soaked with R406: (i) the side chain of the
highly conserved Lys is disordered and not forming a hydrogen bond to R406 and
(ii) the DFG Asp side chain is pointing away from and not towards R406. The
novel protein-ligand interactions and protein conformational changes revealed in
these structures guide the rational design and structure-based optimization of
second-generation spleen tyrosine kinase inhibitors.
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