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@ARTICLE{Pietropaolo:861846,
      author       = {Pietropaolo, Adriana and Magrì, Antonio and Greco,
                      Valentina and Losasso, Valeria and La Mendola, Diego and
                      Sciuto, Sebastiano and Carloni, Paolo and Rizzarelli,
                      Enrico},
      title        = {{B}inding of {Z}n({II}) to {T}ropomyosin {R}eceptor
                      {K}inase {A} in {C}omplex with {I}ts {C}ognate {N}erve
                      {G}rowth {F}actor: {I}nsights from {M}olecular {S}imulation
                      and in {V}itro {E}ssays},
      journal      = {ACS chemical neuroscience},
      volume       = {9},
      number       = {5},
      issn         = {1948-7193},
      address      = {Washington, DC},
      publisher    = {ACS Publ.},
      reportid     = {FZJ-2019-02272},
      pages        = {1095 - 1103},
      year         = {2018},
      abstract     = {The binding of the human nerve growth factor (NGF) protein
                      to tropomyosin receptor kinase A (TrkA) is associated with
                      Alzhemeir’s development. Owing to the large presence of
                      zinc(II) ions in the synaptic compartments, the zinc ions
                      might be bound to the complex in vivo. Here, we have
                      identified a putative zinc binding site using a combination
                      of computations and experiments. First, we have predicted
                      structural features of the NGF/TrkA complex in an aqueous
                      solution by molecular simulation. Metadynamics free energy
                      calculations suggest that these are very similar to those in
                      the X-ray structure. Here, the “crab” structure of the
                      NGF shape binds tightly to two TrkA “pincers”. Transient
                      conformations of the complex include both more extended and
                      more closed conformations. Interestingly, the latter
                      features facial histidines (His60 and His61) among the
                      N-terminal D1–D3 domains, each of which is a potential
                      binding region for biometals. This suggests the presence of
                      a four-His Zn binding site connecting the two chains. To
                      address this issue, we investigated the binding of a D1–D3
                      domains’ peptide mimic by stability constant and nuclear
                      magnetic resonance measurements, complemented by density
                      functional theory-based calculations. Taken together, these
                      establish unambiguously a four-His coordination of the metal
                      ion in the model systems, supporting the presence of our
                      postulated binding site in the NGF/TrkA complex.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {574 - Theory, modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29281262},
      UT           = {WOS:000432752400022},
      doi          = {10.1021/acschemneuro.7b00470},
      url          = {https://juser.fz-juelich.de/record/861846},
}