title: Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.
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.
authors.affiliation: Laboratories of Molecular Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: T
authors.initials: T
authors.lastname: Schindler
authors.forename: W
authors.initials: W
authors.lastname: Bornmann
authors.forename: P
authors.initials: P
authors.lastname: Pellicena
authors.forename: W T
authors.initials: WT
authors.lastname: Miller
authors.forename: B
authors.initials: B
authors.lastname: Clarkson
authors.forename: J
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D010879:Piperazines; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl