title: Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.
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.
authors.affiliation: University of Oxford, Structural Genomics Consortium, Botnar Research Centre, Oxford OX3 7LD, United Kingdom. jeyanthy.eswaran@sgc.ox.ac.uk <jeyanthy.eswaran@sgc.ox.ac.uk>
authors.forename: Jeyanthy
authors.initials: J
authors.lastname: Eswaran
authors.forename: Wen Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Judit E
authors.initials: JE
authors.lastname: Debreczeni
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Andrew
authors.initials: A
authors.lastname: Turnbull
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Sean W
authors.initials: SW
authors.lastname: Deacon
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D003461:Crystallography; D008969:Molecular Sequence Data; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011687:Purines / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D017346:Protein Serine-Threonine Kinases