The tyrosine kinase Fyn is a member of the Src kinase family. Besides the role of Fyn in T cell signal transduction in concert with Lck, its excess activity in the brain is involved with conditions such as Alzheimer's and Parkinson's diseases. Therefore, inhibition of Fyn kinase may help counteract these nervous system disorders. Here, we solved the crystal structure of the human Fyn kinase domain complexed with staurosporine, a potent kinase inhibitor, at 2.8 angstrom resolution. Staurosporine binds to the ATP-binding site of Fyn in a similar manner as in the Lck- and Csk-complexes. The small structural differences in the staurosporine-binding and/or -unbinding region among the three kinase domains may help obtaining the selective inhibitors against the respective kinases. (c) 2006 Elsevier Inc. All rights reserved.