Towards a pharmacophore for amyloid.

TitleTowards a pharmacophore for amyloid.
Publication TypeJournal Article
Year of Publication2011
AuthorsLandau, M, Sawaya MR, Faull KF, Laganowsky A, Jiang L, Sievers SA, Liu J, Barrio JR, Eisenberg D
JournalPLoS biology
Volume9
Issue6
Paginatione1001080
Date Published2011 Jun
ISSN1545-7885
Keywords2-Naphthylamine, Acrylonitrile, Amino Acid Sequence, Amyloid, Amyloidogenic Proteins, Binding Sites, Curcumin, Models, Molecular, Molecular Sequence Data, Protein Conformation, tau Proteins
Abstract

Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases.

Alternate JournalPLoS Biol.