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PDBsum entry 1qcf
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Tyrosine kinase
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PDB id
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1qcf
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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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Crystal structure of hck in complex with a src family-Selective tyrosine kinase inhibitor.
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Authors
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T.Schindler,
F.Sicheri,
A.Pico,
A.Gazit,
A.Levitzki,
J.Kuriyan.
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Ref.
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Mol Cell, 1999,
3,
639-648.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the autoinhibited form of Hck has been determined at
2.0 A resolution, in complex with a specific pyrazolo pyrimidine-type inhibitor,
PP1. The activation segment, a key regulatory component of the catalytic domain,
is unphosphorylated and is visualized in its entirety. Tyr-416, the site of
activating autophosphorylation in the Src family kinases, is positioned such
that access to the catalytic machinery is blocked. PP1 is bound at the
ATP-binding site of the kinase, and a methylphenyl group on PP1 is inserted into
an adjacent hydrophobic pocket. The enlargement of this pocket in autoinhibited
Src kinases suggests a route toward the development of inhibitors that are
specific for the inactive forms of these proteins.
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Figure 4.
Figure 4. Interdependence of the Conformations of Helix αC
and the Activation SegmentThe catalytic domain of inactive Hck
is shown superimposed on that of active Lck ([45]) (A) and of
inactive Cdk2 (B) ( [6]). The structural alignments are based on
the C-terminal lobe in (A) and on the β strands in the
N-terminal lobe of the kinase domains in (B). Helix αC (α1 in
Cdk2) and the activation segment are colored in blue, red, and
green for Hck, Lck, and Cdk2, respectively. The figure was
generated using RIBBONS ( [5]).
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Figure 7.
Figure 7. PP1 Leaves Unfilled a Cavity in Inactive Hck(A)
Structure of the PP1-binding region in inactive Hck. PP1 binding
creates a cavity (yellow surface) in the back of the ATP-binding
site, where two well-ordered water molecules (W1 and W2) are
found.(B) The same cavity (yellow) viewed from the top of the
N-terminal lobe of the catalytic domain. The collapse of this
cavity in active Lck is indicated by showing helix αC as found
in the structure of Lck (PDB code 3lck; [45]), drawn in orange.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(1999,
3,
639-648)
copyright 1999.
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