Download MendeleyCrystal Structures of the P21-Activated Kinases Pak4, Pak5, and Pak6 Reveal Catalytic Domain Plasticity of Active Group II Paks.
Eswaran, J., Lee, W.H., Debreczeni, J.E., Filippakopoulos, P., Turnbull, A., Fedorov, O., Deacon, S.W., Peterson, J.R., Knapp, S.(2007) Structure 15: 201
- PubMed: 17292838
- DOI: https://doi.org/10.1016/j.str.2007.01.001
- Primary Citation of Related Structures:
2BVA, 2C30, 2CDZ, 2F57 - PubMed Abstract:
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.
Organizational Affiliation:
University of Oxford, Structural Genomics Consortium, Botnar Research Centre, Oxford OX3 7LD, United Kingdom. [email protected]
