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@ARTICLE{Lunev:421070,
      author       = {Lunev, Sergey and Butzloff, Sabine and Romero, Atilio R.
                      and Linzke, Marleen and Batista, Fernando A. and Meissner,
                      Kamila A. and Müller, Ingrid B. and Adawy, Alaa and
                      Wrenger, Carsten and Groves, Matthew R.},
      title        = {{O}ligomeric interfaces as a tool in drug discovery:
                      {S}pecific interference with activity of malate
                      dehydrogenase of {P}lasmodium falciparum in vitro},
      journal      = {PLOS ONE},
      volume       = {13},
      number       = {4},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {PUBDB-2019-01835},
      pages        = {e0195011 -},
      year         = {2018},
      abstract     = {Malaria remains a major threat to human health, as strains
                      resistant to current therapeutics are discovered. Efforts in
                      finding new drug targets are hampered by the lack of
                      sufficiently specific tools to provide target validation
                      prior to initiating expensive drug discovery projects. Thus,
                      new approaches that can rapidly enable drug target
                      validation are of significant interest.In this manuscript we
                      present the crystal structure of malate dehydrogenase from
                      Plasmodium falciparum (PfMDH) at 2.4 Å resolution and
                      structure-based mutagenic experiments interfering with the
                      inter-oligomeric interactions of the enzyme. We report
                      decreased thermal stability, significantly decreased
                      specific activity and kinetic parameters of PfMDH mutants
                      upon mutagenic disruption of either oligomeric interface. In
                      contrast, stabilization of one of the interfaces resulted in
                      increased thermal stability, increased substrate/cofactor
                      affinity and hyperactivity of the enzyme towards malate
                      production at sub-millimolar substrate concentrations.
                      Furthermore, the presented data show that our designed PfMDH
                      mutant could be used as specific inhibitor of the wild type
                      PfMDH activity, as mutated PfMDH copies were shown to be
                      able to self-incorporate into the native assembly upon
                      introduction in vitro, yielding deactivated mutant:wild-type
                      species. These data provide an insight into the role of
                      oligomeric assembly in regulation of PfMDH activity and
                      reveal that recombinant mutants could be used as probe tool
                      for specific modification of the wild type PfMDH activity,
                      thus offering the potential to validate its druggability in
                      vivo without recourse to complex genetics or initial tool
                      compounds. Such tool compounds often lack specificity
                      between host or pathogen proteins (or are toxic in in vivo
                      trials) and result in difficulties in assessing cause and
                      effect—particularly in cases when the enzymes of interest
                      possess close homologs within the human host. Furthermore,
                      our oligomeric interference approach could be used in the
                      future in order to assess druggability of other challenging
                      human pathogen drug targets.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      experiment   = {EXP:(DE-H253)D-K1.1-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29694407},
      UT           = {WOS:000430802400020},
      doi          = {10.1371/journal.pone.0195011},
      url          = {https://bib-pubdb1.desy.de/record/421070},
}