title: Towards a pharmacophore for amyloid.
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.
authors.affiliation: Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, Department of Biological Chemistry, University of California, Los Angeles, California, United States of America.
authors.forename: Meytal
authors.initials: M
authors.lastname: Landau
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.forename: Arthur
authors.initials: A
authors.lastname: Laganowsky
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Sievers
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Barrio
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000181:Acrylonitrile / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D058227:Amyloidogenic Proteins; D001665:Binding Sites; D003474:Curcumin / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016875:tau Proteins / Q000737:chemistry
chemical_list: C116723:2-(1,1-dicyanopropenyl-2-)-6-dimethylaminonaphthaleney; D000682:Amyloid; D058227:Amyloidogenic Proteins; D016875:tau Proteins; D015081:2-Naphthylamine; D003474:Curcumin; D000181:Acrylonitrile