Woods, LA, Platt, GW, Hellewell, AL et al. (4 more authors) (2011) Ligand binding to distinct states diverts aggregation of an amyloid-forming protein. Nature Chemical Biology, 7. 730 - 739. ISSN 1552-4469
Abstract
Although small molecules that modulate amyloid formation in vitro have been identified, significant challenges remain in determining precisely how these species act. Here we describe the identification of rifamycin SV as a potent inhibitor of β(2) microglobulin (β(2)m) fibrillogenesis when added during the lag time of assembly or early during fibril elongation. Biochemical experiments demonstrate that the small molecule does not act by a colloidal mechanism. Exploiting the ability of electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) to resolve intermediates of amyloid assembly, we show instead that rifamycin SV inhibits β(2)m fibrillation by binding distinct monomeric conformers, disfavoring oligomer formation and diverting the course of assembly to the formation of spherical aggregates. The results demonstrate the power of ESI-IMS-MS to identify specific protein conformers as targets for intervention in fibrillogenesis using small molecules and reveal a mechanism of action in which ligand binding diverts unfolded protein monomers toward alternative assembly pathways.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2011, Nature Publishing Group. This is an author produced version of a paper published in Nature Chemical Biology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | β 2 -microglobulin; amyloid; rifamycin SV; oligomers; NMR; ESI-MS |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Feb 2015 12:08 |
Last Modified: | 16 Nov 2016 05:13 |
Published Version: | http://dx.doi.org/10.1038/nchembio.635 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/nchembio.635 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83115 |