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ESI-IMS–MS: A method for rapid analysis of protein aggregation and its inhibition by small molecules

Author:
Young, Lydia M., Saunders, Janet C., Mahood, Rachel A., Revill, Charlotte H., Foster, Richard J., Ashcroft, Alison E., Radford, Sheena E.
Source:
Methods 2016 v.95 pp. 62-69
ISSN:
1046-2023
Subject:
amyloid, ligands, rapid methods, spectroscopy, therapeutics
Abstract:
Electrospray ionisation-ion mobility spectrometry–mass spectrometry (ESI-IMS–MS) is a powerful method for the study of conformational changes in protein complexes, including oligomeric species populated during protein self-aggregation into amyloid fibrils. Information on the mass, stability, cross-sectional area and ligand binding capability of each transiently populated intermediate, present in the heterogeneous mixture of assembling species, can be determined individually in a single experiment in real-time. Determining the structural characterisation of oligomeric species and alterations in self-assembly pathways observed in the presence of small molecule inhibitors is of great importance, given the urgent demand for effective therapeutics. Recent studies have demonstrated the capability of ESI-IMS–MS to identify small molecule modulators of amyloid assembly and to determine the mechanism by which they interact (positive, negative, non-specific binding, or colloidal) in a high-throughput format. Here, we demonstrate these advances using self-assembly of Aβ40 as an example, and reveal two new inhibitors of Aβ40 fibrillation.
Agid:
5538316