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PDBsum entry 1byg
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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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Structure of the protein tyrosine kinase domain of c-Terminal src kinase (csk) in complex with staurosporine.
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Authors
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M.B.Lamers,
A.A.Antson,
R.E.Hubbard,
R.K.Scott,
D.H.Williams.
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Ref.
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J Mol Biol, 1999,
285,
713-725.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the kinase domain of C-terminal Src kinase (CSK) has
been determined by molecular replacement, co-complexed with the protein kinase
inhibitor staurosporine (crystals belong to the space group P21212 with a=44.5
A, b=120.6 A, c=48.3 A). The final model of CSK has been refined to an R-factor
of 19.9 % (Rfree=28.7 %) at 2.4 A resolution. The structure consists of a small,
N-terminal lobe made up mostly of a beta-sheet, and a larger C-terminal lobe
made up mostly of alpha-helices. The structure reveals atomic details of
interactions with staurosporine, which binds in a deep cleft between the lobes.
The polypeptide chain fold of CSK is most similar to c-Src, Hck and fibroblast
growth factor receptor 1 kinase (FGFR1K) and most dissimilar to insulin receptor
kinase (IRK).Interactions between the N and C-terminal lobe are mediated by the
bound staurosporine molecule and by hydrogen bonds. In addition, there are
several water molecules forming lobe-bridging hydrogen bonds, which may be
important for maintaining the catalytic integrity of the kinase. Furthermore,
the conserved Lys328 and Glu267 residues utilise water in the formation of a
molecular pivot which is essential in allowing relative movement of the N and
C-terminal lobes. An analysis of the residues around the ATP-binding site
reveals structural differences with other protein tyrosine kinases. Most notable
of these are different orientations of the conserved residues Asp332 and Phe333,
suggesting that inhibitor binding proceeds via an induced fit.These structural
observations have implications for understanding protein tyrosine kinase
catalytic mechanisms and for the design of ATP-mimicking inhibitors of protein
kinases.
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Figure 4.
Figure 4. Overlay of the C-terminal domains of IRK and CSK.
The IRK is shown in blue and the CSK in green; the helices are
displayed as cylinders. The regulatory loop is displayed in
purple and the catalytic loop in red. Residue numbers in blue
indicate the IRK insertion loop and the residue numbers in green
indicate the divergence in the CSK hot loop.
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Figure 6.
Figure 6. C^a trace of CSK with the key water molecules and
residues at the lobe junction. Side-by-side stereo image
generated using the smm external display utility in Quanta97.
The side-chain atom colours are: green, carbon; blue, nitrogen;
red, oxygen; the solvent atoms are displayed as red spheres.
Potential hydrogen bonds are displayed as broken white lines.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1999,
285,
713-725)
copyright 1999.
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