% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Kiss:140404,
      author       = {Kiss, Róbert and Csizmadia, Georgina and Solti, Katalin
                      and Keresztes, Attila and Zhu, Max and Pickhardt, Marcus and
                      Mandelkow, Eckhard and Tóth, Gergely},
      title        = {{S}tructural {B}asis of {S}mall {M}olecule {T}argetability
                      of {M}onomeric {T}au {P}rotein.},
      journal      = {ACS chemical neuroscience},
      volume       = {9},
      number       = {12},
      issn         = {1948-7193},
      address      = {Washington, DC},
      publisher    = {ACS Publ.},
      reportid     = {DZNE-2020-06726},
      pages        = {2997 - 3006},
      year         = {2018},
      abstract     = {The therapeutic targeting of intrinsically disordered
                      proteins (IDPs) by small molecules has been a challenge due
                      to their heterogeneous conformational ensembles. A potential
                      therapeutic strategy to alleviate the aggregation of IDPs is
                      to maintain them in their native monomeric state by small
                      molecule binding. This study investigates the structural
                      basis of small molecule druggability of native monomeric Tau
                      whose aggregation is linked to the onset of Tauopathies such
                      as Alzheimer's disease. Initially, two available monomeric
                      conformational ensembles of a shorter Tau construct K18
                      (also termed Tau4RD) were analyzed which revealed striking
                      structural differences between the two ensembles, while
                      similar number of hot spots and small molecule binding sites
                      were identified on monomeric Tau ensembles as on tertiary
                      folded proteins of similar size. Remarkably, some critical
                      fibril forming sequence regions of Tau (V306-K311,
                      V275-K280) participated in hot spot formation with higher
                      frequency compared to other regions. As an example of small
                      molecule binding to monomeric Tau, it was shown that
                      methylene blue (MB) bound to monomeric K18 and full-length
                      Tau selectively with high affinity (Kd = 125.8 nM and 86.6
                      nM, respectively) with binding modes involving Cys291 and
                      Cys322, previously reported to be oxidized in the presence
                      of MB. Overall, our results provide structure-based evidence
                      that Tau can be a viable drug target for small molecules and
                      indicate that specific small molecules may be able to bind
                      to monomeric Tau and influence the way in which the protein
                      interacts among itself and with other proteins.},
      keywords     = {Humans / Intrinsically Disordered Proteins: metabolism /
                      Methylene Blue: metabolism / Molecular Docking Simulation /
                      Molecular Targeted Therapy / Neurofibrillary Tangles:
                      metabolism / Protein Structure, Tertiary / Tauopathies:
                      metabolism / tau Proteins: chemistry / tau Proteins:
                      metabolism / tau Proteins: ultrastructure / Intrinsically
                      Disordered Proteins (NLM Chemicals) / MAPT protein, human
                      (NLM Chemicals) / tau Proteins (NLM Chemicals) / Methylene
                      Blue (NLM Chemicals)},
      cin          = {AG (Eckhard) Mandelkow},
      ddc          = {540},
      cid          = {I:(DE-2719)1013014},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29944336},
      doi          = {10.1021/acschemneuro.8b00182},
      url          = {https://pub.dzne.de/record/140404},
}