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@ARTICLE{Haslbeck:137990,
      author       = {Haslbeck, Veronika and Drazic, Adrian and Eckl, Julia M and
                      Alte, Ferdinand and Helmuth, Martin and Popowicz, Grzegorz
                      and Schmidt, Werner and Braun, Frank and Weiwad, Matthias
                      and Fischer, Gunter and Gemmecker, Gerd and Sattler, Michael
                      and Striggow, Frank and Groll, Michael and Richter, Klaus},
      title        = {{S}elective activators of protein phosphatase 5 target the
                      auto-inhibitory mechanism.},
      journal      = {Bioscience reports},
      volume       = {35},
      number       = {3},
      issn         = {0144-8463},
      address      = {Colchester},
      publisher    = {Portland Press},
      reportid     = {DZNE-2020-04312},
      pages        = {e00210},
      year         = {2015},
      abstract     = {Protein phosphatase 5 (PP5) is an evolutionary conserved
                      serine/threonine phosphatase. Its dephosphorylation activity
                      modulates a diverse set of cellular factors including
                      protein kinases and the microtubule-associated tau protein
                      involved in neurodegenerative disorders. It is
                      auto-regulated by its heat-shock protein (Hsp90)-interacting
                      tetratricopeptide repeat (TPR) domain and its C-terminal
                      α-helix. In the present study, we report the identification
                      of five specific PP5 activators [PP5 small-molecule
                      activators (P5SAs)] that enhance the phosphatase activity up
                      to 8-fold. The compounds are allosteric modulators
                      accelerating efficiently the turnover rate of PP5, but do
                      barely affect substrate binding or the interaction between
                      PP5 and the chaperone Hsp90. Enzymatic studies imply that
                      the compounds bind to the phosphatase domain of PP5. For the
                      most promising compound crystallographic comparisons of the
                      apo PP5 and the PP5-P5SA-2 complex indicate a relaxation of
                      the auto-inhibited state of PP5. Residual electron density
                      and mutation analyses in PP5 suggest activator binding to a
                      pocket in the phosphatase/TPR domain interface, which may
                      exert regulatory functions. These compounds thus may expose
                      regulatory mechanisms in the PP5 enzyme and serve to develop
                      optimized activators based on these scaffolds.},
      keywords     = {Animals / Caenorhabditis elegans Proteins: metabolism /
                      Crystallography, X-Ray / Drug Evaluation, Preclinical:
                      methods / Enzyme Activation: drug effects / HSC70 Heat-Shock
                      Proteins: genetics / HSC70 Heat-Shock Proteins: metabolism /
                      Mutation / Nuclear Magnetic Resonance, Biomolecular /
                      Nuclear Proteins: antagonists $\&$ inhibitors / Nuclear
                      Proteins: chemistry / Nuclear Proteins: metabolism /
                      Phosphoprotein Phosphatases: antagonists $\&$ inhibitors /
                      Phosphoprotein Phosphatases: chemistry / Phosphoprotein
                      Phosphatases: metabolism / Protein Domains / Rats / Small
                      Molecule Libraries: pharmacology / Caenorhabditis elegans
                      Proteins (NLM Chemicals) / HSC70 Heat-Shock Proteins (NLM
                      Chemicals) / Nuclear Proteins (NLM Chemicals) / Small
                      Molecule Libraries (NLM Chemicals) / Phosphoprotein
                      Phosphatases (NLM Chemicals) / protein phosphatase 5 (NLM
                      Chemicals)},
      cin          = {AG Striggow},
      ddc          = {540},
      cid          = {I:(DE-2719)5000045},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26182372},
      pmc          = {pmc:PMC4721540},
      doi          = {10.1042/BSR20150042},
      url          = {https://pub.dzne.de/record/137990},
}