Overview of the crystal structure of JAK2 kinase domain and sequence alignment of the members of the JAK family around the lip region. (A) Ribbon representation of the crystal structure of JAK2 PTK domain in complex with CMP6 (2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one). The N-terminal lobe (residues 840-931) shown in gray comprises a 5-stranded antiparallel β-sheet (β1 to β5) and one α-helix (αC). The COOH-terminal lobe (residues 932-1132) shown in green comprises 8 α-helices (αD-αK), and 3 3/10 helices (3/10B, 3/10C, 3/10D), and 3 pairs of antiparallel β-strands (β7-β8, β6-β9, and β10-β11). The JAK2 lip contains one 3/10 helix (3/10C) and one α-helix (αH) connected by a short linker. The glycine loop is colored in orange, the hinge region between the 2 lobes in yellow, the catalytic loop in blue, the activation loop in red, and the JAK2 lip in dark blue. The bound CMP6 is presented in a ball-and-stick representation with carbon atoms in gray, oxygen atoms in red, nitrogen atoms in blue, and fluoride atom in pink. (B) Amino acid sequence alignment of human JAK2 PTK domain with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region. The secondary structure of JAK2 is illustrated directly above the sequence alignment. Cylinders delineate α-helices. Residues that are conserved among the JAK kinases sequence are highlighted in red. Dark gray boxes indicate residues conserved to at least 75% within the JAK kinase family. Light gray boxes indicate conservatively substituted residues. GenBank accession codes for JAK2, TYK2, JAK3, JAK1 are NP_004963, AAS37680, NP_000206, and NP_002218, respectively.