Orientation of a Diagnostic Ligand Bound to Macroscopically Aligned Amyloid-β Fibrils Determined by Solid-State NMR

Townsend, David John and Hughes, Eleri and Stewart, Katie and Griffin, John Matthew and Radford, Sheena and Middleton, David Andrew (2018) Orientation of a Diagnostic Ligand Bound to Macroscopically Aligned Amyloid-β Fibrils Determined by Solid-State NMR. The Journal of Physical Chemistry Letters, 9 (22). 6611–6615. ISSN 1948-7185

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Abstract

With amyloid diseases poised to become a major health burden in countries with ageing populations, diagnostic molecules that aid the detection of amyloid in vitro and in vivo are of considerable clinical value. Understanding how such ligands recognize their amyloid targets would help to design diagnostics that target specific amyloid types associated with a particular disease, but methods to provide comprehensive information are underdeveloped. Here solid-state NMR is used to determine the molecular orientation of the amyloid diagnostic 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyryl]-benzene (FSB) when bound to fibrils of the Alzheimer’s amyloid-β polypeptide aligned on a planar substrate. The 19F NMR spectrum of the aligned complex reveals that FSB is oriented approximately parallel with the fibril long axis and bridges four hydrogen-bonded β-sheets. In addition to providing atomic details to aid the design of amyloid-specific diagnostics, this approach will also illuminate the molecular mechanisms of accessory molecules in amyloid disease.

Item Type:
Journal Article
Journal or Publication Title:
The Journal of Physical Chemistry Letters
Additional Information:
This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry Letters, copyright © 2018 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jpclett.8b02448
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2500
Subjects:
ID Code:
128544
Deposited By:
Deposited On:
02 Nov 2018 13:30
Refereed?:
Yes
Published?:
Published
Last Modified:
27 Sep 2020 04:54