Discovery of Small Molecules that Inhibit the Disordered Protein, p27Kip1

Iconaru, Luigi I.; Ban, David; Bharatham, Kavitha; Ramanathan, Arvind; Zhang, Weixing; Shelat, Anang A.; Zuo, Jian; Kriwacki, Richard W.

doi:10.1038/srep15686

Title: Discovery of Small Molecules that Inhibit the Disordered Protein, p27^Kip1

Journal Article · Wed Oct 28 00:00:00 EDT 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep15686· OSTI ID:1261472

Iconaru, Luigi I. ^[1]; Ban, David ^[2]; Bharatham, Kavitha ^[3]; Ramanathan, Arvind ^[4]; Zhang, Weixing ^[2]; Shelat, Anang A. ^[3]; Zuo, Jian ^[5]; Kriwacki, Richard W. ^[6]

Dept. of Structural Biology, Memphis, TN (United States); Dept. of Development Neurobiology, Memphis, TN (United States)
Dept. of Structural Biology, Memphis, TN (United States)
St. Jude Children's Research Hospital, Memphis, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Dept. of Development Neurobiology, Memphis, TN (United States)
Dept. of Structural Biology, Memphis, TN (United States); Univ. of Tennessee Health Science Center, Memphis, TN (United States)

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, p27^Kip1 (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).

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); US Department of the Navy, Office of Naval Research (ONR)

Grant/Contract Number:: AC05-00OR22725; R01CA082491; N000140911014; F32GM113290

OSTI ID:: 1261472

Journal Information:: Scientific Reports, Vol. 5, Issue 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 59 works

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