Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors
| Autor: | Morgenstern Kurt A, David R Stover, Xiaotian Zhu, Joseph L. Kim, Huilin Zhao, Paul E. Rose, John Newcomb, Leticia M Toledo |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Pyridines medicine.drug_class kinase Adenylyl Imidodiphosphate Molecular Sequence Data Biology Crystallography X-Ray SH3 domain Adenosine Triphosphate Structural Biology medicine Humans Staurosporine Amino Acid Sequence Lymphocytes Enzyme Inhibitors Phosphotyrosine Molecular Biology Tyrosine-protein kinase CSK Molecular Structure Kinase Hydrogen Bonding AMP-PNP Protein kinase inhibitor Ligand (biochemistry) PP2 Cell biology Lck staurosporine Src family src-Family Kinases Biochemistry Lymphocyte Specific Protein Tyrosine Kinase p56(lck) X-ray structure Sequence Alignment Tyrosine kinase Protein Binding Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Structure. 7(6):651-661 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/s0969-2126(99)80086-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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