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@ARTICLE{Li:827728,
      author       = {Li, Jinyu and Vervoorts, Jörg and Carloni, Paolo and
                      Rossetti, Giulia and Lüscher, Bernhard},
      title        = {{S}tructural prediction of the interaction of the tumor
                      suppressor p27$^{{KIP}1}$ with cyclin {A}/{CDK}2 identifies
                      a novel catalytically relevant determinant},
      journal      = {BMC bioinformatics},
      volume       = {18},
      number       = {1},
      issn         = {1471-2105},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {FZJ-2017-01836},
      pages        = {15},
      year         = {2017},
      abstract     = {Background The cyclin-dependent kinase 2 (CDK2) together
                      with its cyclin E and A partners is a central regulator of
                      cell growth and division. Deregulation of CDK2 activity is
                      associated with diseases such as cancer. The analysis of
                      substrates identified S/T-P-X-R/K/H as the CDK2 consensus
                      sequence. The crystal structure of cyclin A/CDK2 with a
                      short model peptide supports this sequence and identifies
                      key interactions. However, CDKs use additional determinants
                      to recognize substrates, including the RXL motif that is
                      read by the cyclin subunits. We were interested to determine
                      whether additional amino acids beyond the minimal consensus
                      sequence of the well-studied substrate and tumor suppressor
                      p27KIP1 were relevant for catalysis.ResultsTo address
                      whether additional amino acids, close to the minimal
                      consensus sequence, play a role in binding, we investigate
                      the interaction of cyclin A/CDK2 with an in vivo cellular
                      partner and CDK inhibitor p27KIP1. This protein is an
                      intrinsically unfolded protein and, in particular, the
                      C-terminal half of the protein has not been accessible to
                      structural analysis. This part harbors the CDK2
                      phosphorylation site. We used bioinformatics tools,
                      including MODELLER, iTASSER and HADDOCK, along with partial
                      structural information to build a model of the C-terminal
                      region of p27KIP1 with cyclin A/CDK2. This revealed novel
                      interactions beyond the consensus sequence with a proline
                      and a basic amino acid at the P + 1 and the P + 3
                      sites, respectively. We suggest that the lysine at P + 2
                      might regulate the reversible association of the second
                      counter ion in the active site of CDK2. The arginine at
                      P + 7 interacts with both cyclin A and CDK2 and is
                      important for the catalytic turnover rate.ConclusionOur
                      modeling identifies additional amino acids in p27KIP1 beyond
                      the consensus sequence that contribute to the efficiency of
                      substrate phosphorylation.},
      cin          = {IAS-5 / INM-9 / JSC},
      ddc          = {004},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511)},
      pid          = {G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000392170400003},
      pubmed       = {pmid:28056778},
      doi          = {10.1186/s12859-016-1411-0},
      url          = {https://juser.fz-juelich.de/record/827728},
}