Ribbon diagram of the Jak3 kinase domain and sequence alignment of Jak family members. (A) Overview of the crystal structure of the catalytic domain of Jak3 in complex with tetrahydro-staurosporine AFN941. β-Strands are shown as arrows and α-helices as coils. The glycine-rich loop is colored purple and the activation-loop is blue. The novel αFG helix is colored orange. The N-lobe, C-lobe, and C-helix are indicated. Phosphorylated tyrosines pTyr980 and pTyr981 are shown in stick form. The staurosporine analog is shown as space-filling spheres with carbon atoms colored yellow. (B) Ribbon diagram as in panel A but with the view rotated by 90°. (C) Sequence alignment for the kinase (JH1) domains of Jak3, Jak1, Jak2, and Tyk2; the JH2 domain of Jak3; and the kinase domains of c-Src and epidermal growth factor receptor (EGFR). The numbering and secondary structure assignments for Jak3 crystal structure are indicated. β-Strands are indicated as arrows, α-helices as cylinders, and loops as lines. The activation loop is indicated in red, and the novel helix αFG in orange. The N-lobe is denoted by green secondary structure assignments and the C-lobe with blue. Residues that interact with the staurosporine analog AFN941 are indicated by green boxes. The catalytically important residues Lys855, Glu871 are boxed in red as are the phosphorylated tyrosine residues pTyr980 and pTyr981. GenBank accession codes for Jak1, Jak2, Jak3, Tyk2, c-Src, and EGFR are NP_002218, NP_004963, NP_000206, AAS37680, AAH11566, and NP_005219, respectively.