Discovery of Small Molecules that Inhibit the Disordered Protein, p27(Kip1).

Abstract:

:Disordered proteins 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). 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).

journal_name

Sci Rep

journal_title

Scientific reports

authors

Iconaru LI,Ban D,Bharatham K,Ramanathan A,Zhang W,Shelat AA,Zuo J,Kriwacki RW

doi

10.1038/srep15686

subject

Has Abstract

pub_date

2015-10-28 00:00:00

pages

15686

issn

2045-2322

pii

srep15686

journal_volume

5

pub_type

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