Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase Academic Article Article uri icon

Overview

MeSH Major

  • Neoplasm Proteins
  • Neoplasms
  • Neovascularization, Pathologic
  • Proteome
  • Proteomics

abstract

  • The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.

publication date

  • September 15, 2000

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1126/science.289.5486.1938

PubMed ID

  • 10988075

Additional Document Info

start page

  • 1938

end page

  • 42

volume

  • 289

number

  • 5486