Boehmer, Frank D. and Karagyozov, Luchezar and Uecker, Andrea and Serve, Hubert and Botzki, Alexander and Mahboobi, Siavosh and Dove, Stefan (2003) A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP site inhibitor STI-571. JOURNAL OF BIOLOGICAL CHEMISTRY, 278 (7). pp. 5148-5155. ISSN 0021-9258
Full text not available from this repository.Abstract
The tyrosine kinase inhibitor STI-571 potently blocks BCR-Abl, platelet-derived growth factor (PDGF) alpha- and beta-receptors, and c-Kit kinase activity. Flt3, a receptor tyrosine kinase closely related to PDGF receptors and c-Kit is, however, not inhibited by STI-571. Sequence alignments of different kinases and indications from the crystal structure of the STI-571 Abl kinase complex revealed amino acid residues that are probably crucial for this activity profile. It was predicted that Flt3 Phe-691 in the 135 strand may sterically prevent interaction with STI-571. The point mutants Flt3 F691T and PDGFbeta-receptor T681F were constructed, and kinase assays showed that the Flt3 mutant but not the PDGFbeta-receptor mutant is inhibited by STI-571. Docking of STI-571 into computer models of the PDGFbeta-receptor and Flt3 kinase domains and comparison with the crystal structure of the STI-571 Abl kinase complex indicated very similar binding sites among the three nonphosphorylated kinases, suggesting corresponding courses of their Asp-Phe-Gly motifs and activation loops. Accordingly, we observed reduced sensitivity of preactivated compared with nonactivated PDGFR-beta for the inhibition by STI-571. Courses of the activation loop that collide with STI-571 binding explain its inactivity at other kinases as the insulin receptor. The binding site models of PDGFR-beta and Flt3 were applied to predict structural approaches for more selective PDGFbeta-receptor inhibitors.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR RECEPTOR; PHENYLAMINO-PYRIMIDINE PAP; CRYSTAL-STRUCTURE; SELECTIVE INHIBITORS; SIGNAL-TRANSDUCTION; HEMATOPOIETIC-CELLS; INSULIN-RECEPTOR; PROTEIN-KINASES; DOMAIN; PHOSPHORYLATION; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Aug 2021 11:31 |
| Last Modified: | 24 Aug 2021 11:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/39278 |
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