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.
Highlights
The challenge of developing chemical interventions for Alzheimer’s disease has proceeded in a virtual vacuum of information about the three-dimensional structures of the two proteins most widely accepted as being involved in the etiology
The KLVFFA segment from Ab contains apolar residues that participate in a hydrophobic spine in Ab fibers and itself acts as an inhibitor of Ab fibrillation [28,29]
We previously determined the atomic structure of the KLVFFA segment in three crystal forms; all show the common steric zipper motif associated with amyloid fibers (Colletier et al unpublished results)
Summary
The challenge of developing chemical interventions for Alzheimer’s disease has proceeded in a virtual vacuum of information about the three-dimensional structures of the two proteins most widely accepted as being involved in the etiology. These are amyloid-beta (Ab) and tau [1,2]. Curcumin and various antibiotics are a few of many fiber inhibitors that inhibit oligomer formation [7,9,10], supporting a common underlying structure in fibers and oligomers Despite this progress, until now there have been no atomic-level structures showing how small molecules bind to amyloid and, no means for structure-based design of specific binders
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