Journal
STRUCTURE
Volume 15, Issue 2, Pages 201-213Publisher
CELL PRESS
DOI: 10.1016/j.str.2007.01.001
Keywords
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Funding
- NCI NIH HHS [T32 CA009035] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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 alpha C, a key regulatory element of kinase function, resulted in an additional helical turn at the alpha C 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, aC, and the activation segment and firmly anchor aC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.
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