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@ARTICLE{Cong:820508,
      author       = {Cong, Xiaojing and Cremer, Christian and Nachreiner, Thomas
                      and Barth, Stefan and Carloni, Paolo},
      title        = {{E}ngineered human angiogenin mutations in the placental
                      ribonuclease inhibitor complex for anticancer therapy:
                      {I}nsights from enhanced sampling simulations},
      journal      = {Protein science},
      volume       = {25},
      number       = {8},
      issn         = {0961-8368},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {FZJ-2016-05801},
      pages        = {1451 - 1460},
      year         = {2016},
      abstract     = {Targeted human cytolytic fusion proteins (hCFPs) represent
                      a new generation of immunotoxins (ITs) for the specific
                      targeting and elimination of malignant cell populations.
                      Unlike conventional ITs, hCFPs comprise a human/humanized
                      target cell-specific binding moiety (e.g., an antibody or a
                      fragment thereof) fused to a human proapoptotic protein as
                      the cytotoxic domain (effector domain). Therefore, hCFPs are
                      humanized ITs expected to have low immunogenicity. This
                      reduces side effects and allows long-term application. The
                      human ribonuclease angiogenin (Ang) has been shown to be a
                      promising effector domain candidate. However, the
                      application of Ang-based hCFPs is largely hampered by the
                      intracellular placental ribonuclease inhibitor (RNH1). It
                      rapidly binds and inactivates Ang. Mutations altering Ang's
                      affinity for RNH1 modulate the cytotoxicity of Ang-based
                      hCFPs. Here we perform in total 2.7 µs replica-exchange
                      molecular dynamics simulations to investigate some of these
                      mutations—G85R/G86R (GGRRmut), Q117G (QGmut), and
                      G85R/G86R/Q117G (GGRR/QGmut). GGRRmut turns out to perturb
                      greatly the overall Ang-RNH1 interactions, whereas QGmut
                      optimizes them. Combining QGmut with GGRRmut compensates the
                      effects of the latter. Our results explain the in vitro
                      finding that, while Ang GGRRmut-based hCFPs resist RNH1
                      inhibition remarkably, Ang WT- and Ang QGmut-based ones are
                      similarly sensitive to RNH1 inhibition, whereas Ang
                      GGRR/QGmut-based ones are only slightly resistant. This work
                      may help design novel Ang mutants with reduced affinity for
                      RNH1 and improved cytotoxicity.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000380068700009},
      pubmed       = {pmid:27110669},
      doi          = {10.1002/pro.2941},
      url          = {https://juser.fz-juelich.de/record/820508},
}