STAUROSPORINE-INDUCED CONFORMATIONAL-CHANGES OF CAMP-DEPENDENT PROTEIN-KINASE CATALYTIC SUBUNIT EXPLAIN INHIBITORY POTENTIAL

Background: Staurosporine inhibits most protein kinases at low nanomol ar concentrations. As most tyrosine kinases, along with many serine/th reonine kinases, are either proto oncoproteins or are involved in onco genic signaling, the development of protein kinase inhibitors is a pri mary goal of cancer research. Staurosporine and many of its derivative s have significant biological effects, and are being tested as antican cer drugs, To understand in atomic detail the mode of inhibition and t he parameters of high-affinity binding of staurosporine to protein kin ases, the molecule was cocrystallized with the catalytic subunit of cA MP-dependent protein kinase, Results: The crystal structure of the pro tein kinase catalytic subunit with staurosporine bound to the adenosin e pocket shows considerable induced-fit rearrangement of the enzyme an d a unique open conformation. The inhibitor mimics several aspects of adenosine binding, including both polar and nonpolar interactions with enzyme residues, and induces conformational changes of neighboring en zyme residues, Conclusions: The results explain the high inhibitory po tency of staurosporine, and also illustrate the flexibility of the pro tein kinase active site. The structure, therefore, is not only useful for the design of improved anticancer therapeutics and signaling drugs , but also provides a deeper understanding of the conformational flexi bility of the protein kinase.