Structurally distinct toxicity inhibitors bind at common loci on β-amyloid fibril.
The accumulation of aggregated β-Amyloid (Aβ) in the brain is a hallmark of Alzheimer's disease and is thought to play a role in the neurotoxicity associated with the disease. The mechanism by which Aβ aggregates induce toxicity is uncertain. Nonetheless, several small molecules have been found to interact with Aβ fibrils and to prevent their toxicity. In this paper we studied the binding of these known toxicity inhibitors to Aβ fibrils, as a means to explore surfaces or loci on Aβ aggregates that may be significant in the mechanism of action of these inhibitors. We believe knowledge of these binding loci will provide insight into surfaces on the Aβ fibrils important in Aβ biological activity. The program DOCK was used to computationally dock the inhibitors to an Aβ fibril. The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39. The docking predictions were experimentally verified using lysine specific chemical modifications and Aβ fibrils mutated at Asn27. We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites. Additionally, our data suggests that three additional Aβ toxicity inhibitors may also bind in one of the sites. Identification of these common binding loci provides targets on the Aβ fibril surface that can be tested in the future for their role in Aβ biological activity.
Keshet
Ben
B
Department of Chemical and Biochemical Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
Gray
Jeffrey J
JJ
Good
Theresa A
TA
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000648:ultrastructure; D001665:Binding Sites; D003224:Congo Red / Q000737:chemistry / Q000494:pharmacology; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D009538:Nicotine / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding
D000682:Amyloid; D005419:Flavonoids; D003224:Congo Red; D009538:Nicotine; C040015:myricetin; D003474:Curcumin