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 Repjournal_title
Scientific reportsauthors
Iconaru LI,Ban D,Bharatham K,Ramanathan A,Zhang W,Shelat AA,Zuo J,Kriwacki RWdoi
10.1038/srep15686subject
Has Abstractpub_date
2015-10-28 00:00:00pages
15686issn
2045-2322pii
srep15686journal_volume
5pub_type
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