Repurposing triphenylmethane dyes to bind to trimers derived from Aß

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dc.contributor.authorSalveson, Patrick J.
dc.contributor.authorHaerianardakani, Sepehr
dc.contributor.authorThuy-Boun, Alexander
dc.contributor.authorYoo, Stan
dc.contributor.authorKreutzer, Adam G.
dc.contributor.authorDemeler, Borries
dc.contributor.authorNowick, James S.
dc.date.accessioned2021-08-24T18:15:07Z
dc.date.available2021-08-24T18:15:07Z
dc.date.issued2018
dc.descriptionAccepted author manuscripten_US
dc.description.abstractSoluble oligomers of the β-amyloid peptide, Aβ, are associated with the progression of Alzheimer’s disease. Although many small molecules bind to these assemblies, the details of how these molecules interact with Aβ oligomers remain unknown. This paper reports that crystal violet, and other C3 symmetric triphenylmethane dyes, bind to C3 symmetric trimers derived from Aβ17–36. Binding changes the color of the dyes from purple to blue, and causes them to fluoresce red when irradiated with green light. Job plot and analytical ultracentrifugation experiments reveal that two trimers complex with one dye molecule. Studies with several triphenylmethane dyes reveal that three N,N-dialkylamino substituents are required for complexation. Several mutant trimers, in which Phe19, Phe20, and Ile31 were mutated to cyclohexylalanine, valine, and cyclohexylglycine, were prepared to probe the triphenylmethane dye binding site. Size exclusion chromatography, SDS-PAGE, and X-ray crystallographic studies demonstrate that these mutations do not impact the structure or assembly of the triangular trimer. Fluorescence spectroscopy and analytical ultracentrifugation experiments reveal that the dye packs against an aromatic surface formed by the Phe20 side chains and is clasped by the Ile31 side chains. Docking and molecular modeling provide a working model of the complex in which the triphenylmethane dye is sandwiched between two triangular trimers. Collectively, these findings demonstrate that the X-ray crystallographic structures of triangular trimers derived from Aβ can be used to guide the discovery of ligands that bind to soluble oligomers derived from Aβ.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationSalveson, P. J., Haerianardakani, S., Thuy-Boun, A., Yoo, S., Kreutzer, A. G., Demeler, B., & Nowick, J. S. (2018). Repurposing triphenylmethane dyes to bind to trimers derived from Aß. Journal of the American Chemical Society, 2018, 140(37), 11745-11754. https://doi.org/10.1021/jacs.8b06568en_US
dc.identifier.urihttps://hdl.handle.net/10133/6011
dc.language.isoen_USen_US
dc.publisherAmerican Chemical Societyen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of California Irvineen_US
dc.publisher.institutionUniversity of Texas Health Science Center at San Antonioen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1021/jacs.8b06568en_US
dc.subjectDyesen_US
dc.subjectTriphenylmethane dyes
dc.subject.lcshVat dyes
dc.subject.lcshPeptides
dc.subject.lcshProteins
dc.subject.lcshPigments
dc.subject.lcshCrystals
dc.subject.lcshFluorescence
dc.subject.lcshOligomers
dc.titleRepurposing triphenylmethane dyes to bind to trimers derived from Aßen_US
dc.typeBooken_US
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