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PDBsum entry 1fpu
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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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Structural mechanism for sti-571 inhibition of abelson tyrosine kinase.
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Authors
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T.Schindler,
W.Bornmann,
P.Pellicena,
W.T.Miller,
B.Clarkson,
J.Kuriyan.
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Ref.
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Science, 2000,
289,
1938-1942.
[DOI no: ]
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PubMed id
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Abstract
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The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic
myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is
effective in the treatment of CML. We report the crystal structure of the
catalytic domain of Abl, complexed to a variant of STI-571. Critical to the
binding of STI-571 is the adoption by the kinase of an inactive conformation, in
which a centrally located "activation loop" is not phosphorylated. The
conformation of this loop is distinct from that in active protein kinases, as
well as in the inactive form of the closely related Src kinases. These results
suggest that compounds that exploit the distinctive inactivation mechanisms of
individual protein kinases can achieve both high affinity and high specificity.
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Figure 1.
Fig. 1. Crystal structure of the catalytic domain of Abelson
tyrosine kinase complexed with a variant of STI-571. (A)
Structural formula of the Abl inhibitor STI-571 (panel 1) and
the variant (panel 2) used in this crystallographic study. (B)
Ribbon representation of the three-dimensional structure of Abl
kinase domain in complex with the STI-571 variant shown in (A).
The molecular surface of the inhibitor is shown. A central
conserved region of the kinase, the catalytic segment, is shown
in green and the activation loop in magenta. (C) Ribbon
representation of the activation loop of Abl. The polypeptide
backbone of the activation loop is shown in magenta.
Hydrogen-bonding interaction are depicted by dashed lines.
Tyr393 is the site of phosphorylation within the activation
loop. (D) The polypeptide region in the vicinity of the Tyr393
is shown. Superimposed is the peptide substrate (green), as seen
in the structure of insulin receptor tyrosine kinase (IRK)
complexed with peptide substrate (14), and the activation loop
of IRK in the inactive form (light pink) (32). The figure was
generated by superimposing the catalytic segments of the two
kinases.
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Figure 3.
Fig. 3. STI-571 exploits the unique conformation of the
activation loop in the down-regulated form of Abl. Conformation
of the activation loops of Abl and the Src kinases Lck (active)
(16) and Hck (inactive) (11). Also shown is a space-filling
model of the Abl-specific inhibitor. The figure was generated by
superimposing the catalytic segments of the displayed kinases.
The structures of Lck and Hck are representative for the active
and the inactive state of Src-family tyrosine kinases,
respectively. The active form of Abl is expected to resemble
that of Lck. The activation loop is magenta, the catalytic
segment green. The conserved side chains of the Asp-Phe-Gly
motif and the tyrosine residue in the activation loop are shown
in a ball-and-stick representation.
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The above figures are
reprinted
by permission from the AAAs:
Science
(2000,
289,
1938-1942)
copyright 2000.
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