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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 {beta}-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. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, themore » natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds may be required for future amyloid therapies. The structures described here start to define the amyloid pharmacophore, opening the way to structure-based design of improved diagnostics and therapeutics.« less

Authors:
; ; ; ; ; ; ; ;  [1]
  1. (UCLA)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHHHMIDOE - BIOLOGICAL AND ENVIRONMENTAL RESEARCH
OSTI Identifier:
1019125
Resource Type:
Journal Article
Journal Name:
PLoS Biol.
Additional Journal Information:
Journal Volume: 9; Journal Issue: (6) ; 06, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; BINDERS; CAVITIES; CHAINS; CURCUMIN; DESIGN; DISEASES; DYES; ELECTROSTATICS; FIBERS; LYSINE; OPENINGS; PROTEINS

Citation Formats

Landau, Meytal, Sawaya, Michael R., Faull, Kym F., Laganowsky, Arthur, Jiang, Lin, Sievers, Stuart A., Liu, Jie, Barrio, Jorge R., and Eisenberg, David. Towards a Pharmacophore for Amyloid. United States: N. p., 2011. Web. doi:10.1371/journal.pbio.1001080.
Landau, Meytal, Sawaya, Michael R., Faull, Kym F., Laganowsky, Arthur, Jiang, Lin, Sievers, Stuart A., Liu, Jie, Barrio, Jorge R., & Eisenberg, David. Towards a Pharmacophore for Amyloid. United States. doi:10.1371/journal.pbio.1001080.
Landau, Meytal, Sawaya, Michael R., Faull, Kym F., Laganowsky, Arthur, Jiang, Lin, Sievers, Stuart A., Liu, Jie, Barrio, Jorge R., and Eisenberg, David. Fri . "Towards a Pharmacophore for Amyloid". United States. doi:10.1371/journal.pbio.1001080.
@article{osti_1019125,
title = {Towards a Pharmacophore for Amyloid},
author = {Landau, Meytal and Sawaya, Michael R. and Faull, Kym F. and Laganowsky, Arthur and Jiang, Lin and Sievers, Stuart A. and Liu, Jie and Barrio, Jorge R. and Eisenberg, David},
abstractNote = {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 {beta}-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. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds may be required for future amyloid therapies. The structures described here start to define the amyloid pharmacophore, opening the way to structure-based design of improved diagnostics and therapeutics.},
doi = {10.1371/journal.pbio.1001080},
journal = {PLoS Biol.},
number = (6) ; 06, 2011,
volume = 9,
place = {United States},
year = {2011},
month = {9}
}