Molecular rulers: an assessment of distance and spatial relationships of Src tyrosine kinase Sh2 and active site regions
| Autor: | Tae Ryong Lee, David S. Lawrence, Jinkui Niu, Adam A. Profit |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
chemistry.chemical_classification
Binding Sites biology Stereochemistry Active site Peptide Cell Biology Crystallography X-Ray Biochemistry SH3 domain Enzyme activator Enzyme src-Family Kinases chemistry biology.protein Amino Acid Sequence Molecular Biology Tyrosine kinase Linker Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | The Journal of biological chemistry. 276(12) |
| ISSN: | 0021-9258 |
| Popis: | The three-dimensional structures of the inactive conformations of Hck and Src, members of the Src protein-tyrosine kinase family, have recently been described. In both cases, the catalytic domain lies on the opposite face of the enzyme from the SH2 and SH3 domains. The active conformation of these enzymes has not yet been described. Given the known role of the SH2 and SH3 domains in promoting substrate binding, enzyme activation likely reorients the relative spatial arrangement between the SH2/SH3 domains and the active site region. We describe herein a series of "molecular rulers" and their use in assessing the topological and spatial relationships of the SH2 and active site regions of the Src protein-tyrosine kinase. These synthetic compounds contain sequences that are active site-directed (-Glu-Glu-Ile-Ile-(F(5))Phe-, where (F(5))Phe is pentafluorophenylalanine) and SH2-directed (-Tyr(P)-Glu-Glu-Ile-Glu-), separated by a sequence of variable length. The most potent bivalent compound, acetyl-Glu-Glu-Leu-Leu-(F(5))Phe-(GABA)(3)-Tyr(P)-Glu-Glu-Ile-Glu-amide (where GABA is gamma-aminobutyric acid), displays a120-fold enhancement in inhibitory potency relative to the simple monovalent active site-directed species, acetyl-Glu-Glu-Leu-Leu-(F(5))Phe-amide. The short linker length (3 GABA residues) between the active site- and SH2-directed peptide fragments suggests that the corresponding domains on the Src kinase can assume a nearly contiguous spatial arrangement in the active form of the enzyme. |
| Databáze: | OpenAIRE |
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