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1qpd

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{{STRUCTURE_1qpd| PDB=1qpd | SCENE= }}
{{STRUCTURE_1qpd| PDB=1qpd | SCENE= }}
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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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===STRUCTURAL ANALYSIS OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH NON-SELECTIVE AND SRC FAMILY SELECTIVE KINASE INHIBITORS===
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==Overview==
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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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{{ABSTRACT_PUBMED_10404594}}
==About this Structure==
==About this Structure==
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[[Category: Zhu, X.]]
[[Category: Zhu, X.]]
[[Category: Alpha beta fold]]
[[Category: Alpha beta fold]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 08:50:04 2008''

Revision as of 05:50, 28 July 2008

Image:1qpd.png

Template:STRUCTURE 1qpd

STRUCTURAL ANALYSIS OF THE LYMPHOCYTE-SPECIFIC KINASE LCK IN COMPLEX WITH NON-SELECTIVE AND SRC FAMILY SELECTIVE KINASE INHIBITORS

Template:ABSTRACT PUBMED 10404594

About this Structure

1QPD is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors., Zhu X, Kim JL, Newcomb JR, Rose PE, Stover DR, Toledo LM, Zhao H, Morgenstern KA, Structure. 1999 Jun 15;7(6):651-61. PMID:10404594

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