Structural basis for the autoinhibition of c-Abl tyrosine kinase Journal Article
| Authors: | Nagar, B.; Hantschel, O.; Young, M. A.; Scheffzek, K.; Veach, D.; Bornmann, W.; Clarkson, B.; Superti-Furga, G.; Kuriyan, J. |
| Article Title: | Structural basis for the autoinhibition of c-Abl tyrosine kinase |
| Abstract: | c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src. |
| Keywords: | pyridines; protein conformation; imatinib; enzyme inhibition; protein binding; enzyme activity; protein tyrosine kinase; pyrimidines; structure-activity relationship; phosphorylation; enzyme regulation; recombinant fusion proteins; enzyme inhibitors; crystal structure; models, molecular; crystallography, x-ray; piperazines; catalysis; conformation; enzyme binding; proto-oncogene proteins c-abl; priority journal; article; src homology domain; src homology domains; rumex |
| Journal Title: | Cell |
| Volume: | 112 |
| Issue: | 6 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2003-03-21 |
| Start Page: | 859 |
| End Page: | 871 |
| Language: | English |
| DOI: | 10.1016/s0092-8674(03)00194-6 |
| PUBMED: | 12654251 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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