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Mass spectrometry (MS) is widely used to assess the binding of small molecules to proteins and their complexes. In many cases, subtle differences in the stability afforded by binding of ligands to protein assemblies cannot be detected by MS. Here we show that monitoring the unfolding of protein subunits, using ion mobility-MS, allows differentiation of the effects of ligand binding not normally observed by MS alone. Using wild-type and disease-associated variants of tetrameric transthyretin, MS data indicate that populations of the variant protein are less stable than wild-type. Ion mobility-MS, however, is able to show that the natural ligand of transthyretin, thyroxine, provides a larger stability increase to the tetramer composed of variant subunits than to the wild-type protein-ligand complex. Overall, therefore, our results have implications for small-molecule drug design directed at multiprotein targets.

Original publication

DOI

10.1016/j.chembiol.2009.02.008

Type

Journal article

Journal

Chem Biol

Publication Date

24/04/2009

Volume

16

Pages

382 - 390

Keywords

Amyloidosis, Humans, Ligands, Prealbumin, Protein Binding, Protein Folding, Protein Multimerization, Protein Stability, Protein Structure, Quaternary, Protein Subunits, Spectrometry, Mass, Electrospray Ionization, Thyroxine