Work

A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein

Year: 2017

Type: article

Abstract: Intrinsically disordered proteins (IDPs) have roles in myriad biological processes and numerous human diseases. However, kinetic and amplitude information regarding their ground-state conformational fluctuations has remained elusive. We demonstrate using nuclear magnetic resonance (NMR)-based relaxation dispersion that the D2 domain of p27 Kip1, a prototypical IDP, samples multiple discrete, rapidly exchanging conformational states. By combining NMR with mutagenesis and small-angle X-ray scattering (SAXS), we show that these states involve aromatic residue clustering through long-range hydrophobic interactions. Theoretical studies have proposed that small molecules bind promiscuously to IDPs, causing expansion of their conformational landscapes. However, on the basis of previous NMR-based screening results, we show here that compound binding only shifts the populations of states that existed within the ground state of apo p27-D2 without changing the barriers between states. Our results provide atomic resolution insight into how a small molecule binds an IDP and emphasize the need to examine motions on the low microsecond time scale when probing these types of interactions.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.7b01380

Authors: David Ban, Luigi I. Iconaru, Arvind Ramanathan, Jian Zuo, Richard W. Kriwacki

Institutions: St. Jude Children's Research Hospital, Oak Ridge National Laboratory, University of Tennessee Health Science Center

Language: English

Topic: Protein Structure and Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green