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p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix alphaC, a key regulatory element of kinase function, resulted in an additional helical turn at the alphaC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, alphaC, and the activation segment and firmly anchor alphaC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.

Original publication

DOI

10.1016/j.str.2007.01.001

Type

Journal article

Journal

Structure

Publication Date

02/2007

Volume

15

Pages

201 - 213

Keywords

Amino Acid Sequence, Animals, Catalytic Domain, Crystallography, Molecular Sequence Data, Protein Conformation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Purines