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@ARTICLE{Kaschner:829442,
      author       = {Kaschner, Marco and Schillinger, Oliver and Fettweiss, Timo
                      and Nutschel, Christina and Krause, Frank and Fulton,
                      Alexander and Strodel, Birgit and Stadler, Andreas and
                      Jaeger, Karl-Erich and Krauss, Ulrich},
      title        = {{A} combination of mutational and computational scanning
                      guides the design of an artificial ligand-binding controlled
                      lipase},
      journal      = {Scientific reports},
      volume       = {7},
      issn         = {2045-2322},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {FZJ-2017-03146},
      pages        = {42592 -},
      year         = {2017},
      abstract     = {Allostery, i.e. the control of enzyme activity by a small
                      molecule at a location distant from the enzyme’s active
                      site, represents a mechanism essential for sustaining life.
                      The rational design of allostery is a non-trivial task but
                      can be achieved by fusion of a sensory domain, which
                      responds to environmental stimuli with a change in its
                      structure. Hereby, the site of domain fusion is difficult to
                      predict. We here explore the possibility to rationally
                      engineer allostery into the naturally not allosterically
                      regulated Bacillus subtilis lipase A, by fusion of the
                      citrate-binding sensor-domain of the CitA sensory-kinase of
                      Klebsiella pneumoniae. The site of domain fusion was
                      rationally determined based on whole-protein site-saturation
                      mutagenesis data, complemented by computational
                      evolutionary-coupling analyses. Functional assays, combined
                      with biochemical and biophysical studies suggest a mechanism
                      for control, similar but distinct to the one of the parent
                      CitA protein, with citrate acting as an indirect modulator
                      of Triton-X100 inhibition of the fusion protein. Our study
                      demonstrates that the introduction of ligand-dependent
                      regulatory control by domain fusion is surprisingly facile,
                      suggesting that the catalytic mechanism of some enzymes may
                      be evolutionary optimized in a way that it can easily be
                      perturbed by small conformational changes.},
      cin          = {ICS-1 / Neutronenstreuung ; JCNS-1 / ICS-6 / IMET},
      ddc          = {000},
      cid          = {I:(DE-Juel1)ICS-1-20110106 / I:(DE-Juel1)JCNS-1-20110106 /
                      I:(DE-Juel1)ICS-6-20110106 / I:(DE-Juel1)IMET-20090612},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551) /
                      6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623)
                      / 6215 - Soft Matter, Health and Life Sciences (POF3-621) /
                      581 - Biotechnology (POF3-581)},
      pid          = {G:(DE-HGF)POF3-551 / G:(DE-HGF)POF3-6G4 /
                      G:(DE-HGF)POF3-6215 / G:(DE-HGF)POF3-581},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000394417100001},
      doi          = {10.1038/srep42592},
      url          = {https://juser.fz-juelich.de/record/829442},
}