QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online Supporting Material Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nagar, B. Search for Related Content PubMed PubMed Citation Articles by Nagar, B.

---

Supplement: Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application: SESSION 2

c-Abl Tyrosine Kinase and Inhibition by the Cancer Drug Imatinib (Gleevec/STI-571)^1–4,

Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

^* To whom correspondence should be addressed. E-mail: bhushan.nagar{at}mcgill.ca.

The search for specific protein kinase inhibitors is an intense area of research because of the potential for drug development. The small-molecule inhibitor imatinib (Gleevec/STI-571) can specifically inactivate the tyrosine kinase c-Abl, whose normal mechanism of autoinhibition is disrupted in chronic myelogenous leukemia. Crystallographic analysis of c-Abl reveals that imatinib recognizes a distinct inactive conformation of the Abl kinase domain that relies on the mechanism of autoinhibition achieved in the context of a larger fragment of the protein. This mechanism is distinct from that seen in the related Src family kinases, where autoinhibition is achieved through the internal engagement of a C-terminal phosphotyrosine residue by the Src homology 2 domain (SH2) domain. Notably, this phosphotyrosine residue is lacking in c-Abl, where instead autoinhibition is mediated by an interaction between the kinase domain and the N-terminal myristoyl modification. Within the framework of these 2 distinct modes of autoinhibition, the SH3-SH2 unit is structurally conserved between Abl and Src, leading to large conformational differences in their kinase domains. These differences help explain the ability of imatinib to preferentially inhibit Abl over Src.

This article has been cited by other articles:

				K. Takai Introduction to the Transdisciplinary International Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application J. Nutr., June 1, 2007; 137(6): 1501S - 1503S. [Full Text] [PDF]

				Y. Shimomura and S. M. Morris Jr. Biology and Biochemistry: Discussion of Session 2 J. Nutr., June 1, 2007; 137(6): 1548S - 1548S. [Full Text] [PDF]