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The crystal structure of PI3Kγ in complex with Ras has been solved, revealing a significant conformational change and thereby suggesting an allosteric mechanism of activation. Specific differences compared to the complexes of Ras with Raf and RalGDS are highlighted; a loop in the RBD seems to be responsible for these. Particularly, direct contacts of Ras not only with the RBD but also with the catalytic domain of PI3Kγ are established. In addition, the paper shows interesting data on the kinetics of interaction and a mutational analysis of the interaction - including PI3Kγ activation in vivo
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Lei M., Lu W.G., Meng W.Y., Parrini M.C., Eck M.J., Mayer B.J., Harrison S.C. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell. 102:2000;387-397 The crystal structure of the complex between the regulatory and catalytic fragments of PAK1 shows how intramolecular inhibition of the kinase is achieved and suggests a mechanism of activation by binding Cdc42 or Rac. The inhibitory switch (IS) domain at one end blocks the catalytic site and at the other end forms a dimer contact with the IS domain of another PAK molecule. Supported by observations of WASP activation [32,34], a mechanism is suggested whereby Cdc42 or Rac binding leads to major structural rearrangements of the IS domain and thereby release of autoinhibition and dissociation of the dimer.
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A combination of NMR, X-ray and biochemical studies demonstrates the importance of the relationship between conformational dynamics and the interaction between Ras and effectors. Thr35 in Ras is strictly conserved in all small GTPases - not even substitution by serine is tolerated - presumably because of its role in the control of switch dynamics
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