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@ARTICLE{LaSala:820730,
      author       = {La Sala, Giuseppina and Riccardi, Laura and Gaspari,
                      Roberto and Cavalli, Andrea and Hantschel, Oliver and De
                      Vivo, Marco},
      title        = {{HRD} {M}otif as the {C}entral {H}ub of the {S}ignaling
                      {N}etwork for {A}ctivation {L}oop {A}utophosphorylation in
                      {A}bl {K}inase},
      journal      = {Journal of chemical theory and computation},
      volume       = {12},
      number       = {11},
      issn         = {1549-9626},
      address      = {Washington, DC},
      reportid     = {FZJ-2016-05998},
      pages        = {5563 - 5574},
      year         = {2016},
      abstract     = {A number of structural factors modulate the activity of
                      Abelson (Abl) tyrosine kinase, whose deregulation is often
                      related to oncogenic processes. First, only the open
                      conformation of the Abl kinase domain’s activation loop
                      (A-loop) favors ATP binding to the catalytic cleft. In this
                      regard, the trans-autophosphorylation of the Y412 residue,
                      which is located along the A-loop, favors the stability of
                      the open conformation, in turn enhancing Abl activity.
                      Another key factor for full Abl activity is the formation of
                      active conformations of the catalytic DFG motif in the Abl
                      kinase domain. Furthermore, binding of the SH2 domain to the
                      N-lobe of the Abl kinase was recently demonstrated to have a
                      long-range allosteric effect on the stabilization of the
                      A-loop open state. Intriguingly, these distinct structural
                      factors imply a complex signal transmission network for
                      controlling the A-loop’s flexibility and conformational
                      preference for optimal Abl function. However, the exact
                      dynamical features of this signal transmission network
                      structure remain unclear. Here, we report on
                      microsecond-long molecular dynamics coupled with enhanced
                      sampling simulations of multiple Abl model systems, in the
                      presence or absence of the SH2 domain and with the DFG motif
                      flipped in two ways (in or out conformation). Through
                      comparative analysis, our simulations augment the
                      interpretation of the existing Abl experimental data,
                      revealing a dynamical network of interactions that
                      interconnect SH2 domain binding with A-loop plasticity and
                      Y412 autophosphorylation in Abl. This signaling network
                      engages the DFG motif and, importantly, other conserved
                      structural elements of the kinase domain, namely, the
                      EPK-ELK H-bond network and the HRD motif. Our results show
                      that the signal propagation for modulating the A-loop
                      spatial localization is highly dependent on the HRD motif
                      conformation, which thus acts as the central hub of this
                      (allosteric) signaling network controlling Abl activation
                      and function.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      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:000387519400031},
      pubmed       = {pmid:27682200},
      doi          = {10.1021/acs.jctc.6b00600},
      url          = {https://juser.fz-juelich.de/record/820730},
}