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@ARTICLE{Sacerdoti:276857,
      author       = {M. Sacerdoti and L. Z. F. Gross and A. M. Riley and K.
                      Zehnder and A. Ghode and S. Klinke and G. S. Anand and K.
                      Paris and A. Winkel and A. K. Herbrand and H. Y. Godage and
                      G. E. Cozier and E. Süß and J. O. Schulze and D.
                      Pastor-Flores and M. Bollini and M. V. Cappellari and D.
                      Svergun and M. A. Gräwert and P. F. Aramendia and A. E.
                      Leroux and B. V. L. Potter and C. J. Camacho and R. M.
                      Biondi$^*$},
      title        = {{M}odulation of the substrate specificity of the kinase
                      {PDK}1 by distinct conformations of the full-length
                      protein.},
      journal      = {Science signaling},
      volume       = {16},
      number       = {789},
      issn         = {1945-0877},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2023-01169},
      pages        = {eadd3184},
      year         = {2023},
      abstract     = {The activation of at least 23 different mammalian kinases
                      requires the phosphorylation of their hydrophobic motifs by
                      the kinase PDK1. A linker connects the
                      phosphoinositide-binding PH domain to the catalytic domain,
                      which contains a docking site for substrates called the PIF
                      pocket. Here, we used a chemical biology approach to show
                      that PDK1 existed in equilibrium between at least three
                      distinct conformations with differing substrate
                      specificities. The inositol polyphosphate derivative HYG8
                      bound to the PH domain and disrupted PDK1 dimerization by
                      stabilizing a monomeric conformation in which the PH domain
                      associated with the catalytic domain and the PIF pocket was
                      accessible. In the absence of lipids, HYG8 potently
                      inhibited the phosphorylation of Akt (also termed PKB) but
                      did not affect the intrinsic activity of PDK1 or the
                      phosphorylation of SGK, which requires docking to the PIF
                      pocket. In contrast, the small-molecule valsartan bound to
                      the PIF pocket and stabilized a second distinct monomeric
                      conformation. Our study reveals dynamic conformations of
                      full-length PDK1 in which the location of the linker and the
                      PH domain relative to the catalytic domain determines the
                      selective phosphorylation of PDK1 substrates. The study
                      further suggests new approaches for the design of drugs to
                      selectively modulate signaling downstream of PDK1.},
      cin          = {FM01},
      ddc          = {500},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37311034},
      doi          = {10.1126/scisignal.add3184},
      url          = {https://inrepo02.dkfz.de/record/276857},
}