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Title: Discovery of Small Molecules that Inhibit the Disordered Protein, p27Kip1

In disordered proteins we see that they are highly prevalent in biological systems. They control myriad signaling and regulatory processes, and their levels and/or cellular localization are often altered in human disease. In contrast to folded proteins, disordered proteins, due to conformational heterogeneity and dynamics, are not considered viable drug targets. We challenged this paradigm by identifying through NMR-based screening small molecules that bound specifically, albeit weakly, to the disordered cell cycle regulator, p27Kip1 (p27). Moreover, two groups of molecules bound to sites created by transient clusters of aromatic residues within p27. Conserved chemical features within these two groups of small molecules exhibited complementarity to their binding sites within p27, establishing structure-activity relationships for small molecule: disordered protein interactions. Finally, one compound counteracted the Cdk2/cyclin A inhibitory function of p27 in vitro, providing proof-of- principle that small molecules can inhibit the function of a disordered protein (p27) through sequestration in a conformation incapable of folding and binding to a natural regulatory target (Cdk2/cyclin A).
 [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [3] ;  [5] ;  [6]
  1. Dept. of Structural Biology, Memphis, TN (United States); Dept. of Development Neurobiology, Memphis, TN (United States)
  2. Dept. of Structural Biology, Memphis, TN (United States)
  3. St. Jude Children's Research Hospital, Memphis, TN (United States)
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  5. Dept. of Development Neurobiology, Memphis, TN (United States)
  6. Dept. of Structural Biology, Memphis, TN (United States); Univ. of Tennessee Health Science Center, Memphis, TN (United States)
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC05-00OR22725; R01CA082491; N000140911014; F32GM113290
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal Issue: 5; Journal ID: ISSN 2045-2322
Nature Publishing Group
Research Org:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH); Office of Naval Research
Country of Publication:
United States