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PDBsum entry 1xbc
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References listed in PDB file
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Key reference
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Title
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A novel mode of gleevec binding is revealed by the structure of spleen tyrosine kinase.
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Authors
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S.Atwell,
J.M.Adams,
J.Badger,
M.D.Buchanan,
I.K.Feil,
K.J.Froning,
X.Gao,
J.Hendle,
K.Keegan,
B.C.Leon,
H.J.Müller-Dieckmann,
V.L.Nienaber,
B.W.Noland,
K.Post,
K.R.Rajashankar,
A.Ramos,
M.Russell,
S.K.Burley,
S.G.Buchanan.
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Ref.
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J Biol Chem, 2004,
279,
55827-55832.
[DOI no: ]
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PubMed id
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Abstract
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Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for
signaling from immunoreceptors in various hematopoietic cells. Phosphorylation
of two tyrosine residues in the activation loop of the Syk kinase catalytic
domain is necessary for signaling, a phenomenon typical of tyrosine kinase
family members. Syk in vitro enzyme activity, however, does not depend on
phosphorylation (activation loop tyrosine --> phenylalanine mutants retain
catalytic activity). We have determined the x-ray structure of the
unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a
conformation of the activation loop typically seen only in activated,
phosphorylated tyrosine kinases, explaining why Syk does not require
phosphorylation for activation. We also demonstrate that Gleevec (STI-571,
Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and
phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel,
compact cis-conformation that differs dramatically from the binding mode
observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This
finding suggests the existence of two distinct Gleevec binding modes: an
extended, trans-conformation characteristic of tight binding to the inactive
conformation of a protein kinase and a second compact, cis-conformation
characteristic of weaker binding to the active conformation. Finally, the
Syk-bound cis-conformation of Gleevec bears a striking resemblance to the rigid
structure of the nonspecific, natural product kinase inhibitor staurosporine.
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Figure 2.
FIG. 2. Stereo view of alternate Gleevec binding modes.
Gleevec bound to unphosphorylated Abl (green) adopts an
extended, trans-confirmation, which is incompatible with the
phosphorylated/more active confirmation of Abl (blue). Gleevec
binds to the unphosphorylated/active confirmation of Syk
(yellow) in a very different cis-conformation, which is more
compatible with binding to the phosphorylated/more active
conformation of Abl (blue). The key residues are labeled.
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Figure 4.
FIG. 4. A, binding of Gleevec to Syk. Ligand difference
electron density (2 F[observed]-F[calculated]) contoured at 1
 .
B, binding of Gleevec and staurosporine to Syk. Gleevec (yellow)
binding to Syk in the compact cis-conformation mimics the
structure and binding mode of staurosporine (salmon). The key
residues are labeled, and hydrogen bonds are denoted with dashed
lines. The images were prepared with Xfit (25).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
55827-55832)
copyright 2004.
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