Schematic representation of the complex formed between STI-571 (imatinib) and the kinase domain of Abelson tyrosine kinase (Abl). STI-571 (orange with white highlights) spans the width of the kinase (green), wedging itself between the N- and C-lobes and locking the activation loop (red) of Abl into a conformation that mimics substrate binding and blocks the active site of the enzyme. Also shown is the conformation of the activation loop when bound to another tyrosine kinase inhibitor, PD173955 (blue). The blue conformation of the activation loop (similar to the conformation of the activation loop seen in activated tyrosine kinases) clashes with the drug and would prevent binding of STI-571. The figure illustrates how the activation loop must be in the red conformation in order for Abl to accommodate STI-571, thus imparting conformational specificity to a drug that partially obstructs an otherwise generic ATP-binding cleft. For details, see the article by Nagar et al. on page 4236 of this issue.