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PDBsum entry 1qpd
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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 analysis of the lymphocyte-Specific kinase lck in complex with non-Selective and src family selective kinase inhibitors.
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Authors
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X.Zhu,
J.L.Kim,
J.R.Newcomb,
P.E.Rose,
D.R.Stover,
L.M.Toledo,
H.Zhao,
K.A.Morgenstern.
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Ref.
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Structure, 1999,
7,
651-661.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: The lymphocyte-specific kinase Lck is a member of the Src family of
non-receptor tyrosine kinases. Lck catalyzes the initial phosphorylation of
T-cell receptor components that is necessary for signal transduction and T-cell
activation. On the basis of both biochemical and genetic studies, Lck is
considered an attractive cell-specific target for the design of novel T-cell
immunosuppressants. To date, the lack of detailed structural information on the
mode of inhibitor binding to Lck has limited the discovery of novel Lck
inhibitors. RESULTS: We report here the high-resolution crystal structures of an
activated Lck kinase domain in complex with three structurally distinct
ATP-competitive inhibitors: AMP-PNP (a non-selective, non-hydrolyzable ATP
analog); staurosporine (a potent but non-selective protein kinase inhibitor);
and PP2 (a potent Src family selective protein tyrosine kinase inhibitor).
Comparison of these structures reveals subtle but important structural changes
at the ATP-binding site. Furthermore, PP2 is found to access a deep, hydrophobic
pocket near the ATP-binding cleft of the enzyme; this binding pocket is not
occupied by either AMP-PNP or staurosporine. CONCLUSIONS: The potency of
staurosporine against Lck derives in part from an induced movement of the
glycine-rich loop of the enzyme upon binding of this ligand, which maximizes the
van der Waals interactions present in the complex. In contrast, PP2 binds
tightly and selectively to Lck and other Src family kinases by making additional
contacts in a deep, hydrophobic pocket adjacent to the ATP-binding site; the
amino acid composition of this pocket is unique to Src family kinases. The
structures of these Lck complexes offer useful structural insights as they
demonstrate that kinase selectivity can be achieved with small-molecule
inhibitors that exploit subtle topological differences among protein kinases.
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Figure 2.
Figure 2. Schematic representation of the hydrogen-bond
interactions and van der Waals contacts between Lck and bound
ligands: (a) AMP-PNP; (b) staurosporine; (c) PP2. Hydrogen bonds
are represented with dashed lines. The residues of Lck in
contact with the bound ligand are shown.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
651-661)
copyright 1999.
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