Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
Thomas Schindler,1
William Bornmann,3
Patricia Pellicena,4
W. Todd Miller,4
Bayard Clarkson,3
John Kuriyan12*
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.
1 Laboratories of Molecular Biophysics and
2 Howard Hughes Medical Institute, The Rockefeller
University, 1230 York Avenue, New York, NY 10021, USA.
3 Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10021, USA.
4 Department of
Physiology and Biophysics, School of Medicine, State University of New
York at Stony Brook, Stony Brook, NY 11794, USA.
*
To whom correspondence should be addressed. E-mail:
kuriyan{at}rockefeller.edu
