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  Small molecules detected by second-harmonic generation modulate the conformation of monomeric α-synuclein and reduce its aggregation in cell.

Moree, B., Yin, G., Lazaro, D. F., Munari, F., Strohäker, T., Giller, K., et al. (2015). Small molecules detected by second-harmonic generation modulate the conformation of monomeric α-synuclein and reduce its aggregation in cell. Journal of Biological Chemistry, 290(46), 27582-27593. doi:10.1074%2Fjbc.M114.636027.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-447C-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-1CC0-A
Genre: Journal Article

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 Creators:
Moree, B., Author
Yin, G., Author
Lazaro, D. F., Author
Munari, F.1, Author              
Strohäker, T.1, Author              
Giller, K.2, Author              
Becker, S.2, Author              
Outeiro, T. F., Author
Zweckstetter, M.1, Author              
Salafsky, J., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
2Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: drug discovery, Parkinson disease, protein aggregation, protein conformation, protein drug interaction
 Abstract: Proteins are structurally dynamic molecules that perform specialized functions through unique conformational changes accessible in physiological environments. An ability to specifically and selectively control protein function via conformational modulation is an important goal for development of novel therapeutics and studies of protein mechanism in biological networks and disease. Here we applied a second-harmonic generation-based technique for studying protein conformation in solution and in real time to the intrinsically disordered, Parkinson disease related protein α-synuclein. From a fragment library, we identified small molecule modulators that bind to monomeric α-synuclein in vitro and significantly reduce α-synuclein aggregation in a neuronal cell culture model. Our results indicate that the conformation of α-synuclein is linked to the aggregation of protein in cells. They also provide support for a therapeutic strategy of targeting specific conformations of the protein to suppress or control its aggregation.

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Language(s): eng - English
 Dates: 2015-09-222015-11-13
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1074%2Fjbc.M114.636027
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 290 (46) Sequence Number: - Start / End Page: 27582 - 27593 Identifier: -