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  Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01

Vöpel, T., Bravo-Rodriguez, K., Mittal, S., Vachharajani, S., Gnutt, D., Sharma, A., et al. (2017). Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01. Journal of the American Chemical Society, 139(16), 5640-5643. doi:10.1021/jacs.6b11039.

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 Creators:
Vöpel, Tobias1, Author
Bravo-Rodriguez, Kenny2, Author              
Mittal, Sumit2, Author              
Vachharajani, Shivang1, Author
Gnutt, David1, Author
Sharma, Abhishek1, Author
Steinhof, Anne3, Author
Fatoba, Oluwaseun4, Author
Ellrichmann, Gisa4, Author
Nshanian, Michael5, Author
Heid, Christian6, Author
Loo, Josepf A.5, 7, Author
Klärner, Gerrit6, Author
Schrader, Thomas6, Author
Bitan, Gal8, Author
Wanker, Erich E.3, Author
Ebbinghaus, Simon1, Author
Sanchez-Garcia, Elsa2, Author              
Affiliations:
1Department of Physical Chemistry II, Ruhr-University Bochum, 44780 Bochum, Germany, ou_persistent22              
2Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
3Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany, ou_persistent22              
4Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44780 Bochum, Germany, ou_persistent22              
5Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, United States, ou_persistent22              
6Institute of Organic Chemistry, University of Duisburg-Essen, 45141 Essen, Germany, ou_persistent22              
7Department of Biological Chemistry and UCLA/DOE Institute of Genomics and Proteomics, University of California at Los Angeles, Los Angeles, California 90095, United States, ou_persistent22              
8Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095-7334, United States, ou_persistent22              

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 Abstract: Huntington’s disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htte1). Above a threshold of 37 glutamine residues, htte1 starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htte1 (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htte1. Here we identify N17 as a potential target for novel therapeutic intervention using the molecular tweezer CLR01. A combination of biochemical experiments and computer simulations shows that binding of CLR01 induces structural rearrangements within the htte1 monomer and inhibits htte1 aggregation, underpinning the key role of N17 in modulating htte1 toxicity.

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Language(s): eng - English
 Dates: 2017-10-292017-04-132017-04-26
 Publication Status: Published in print
 Pages: 4
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/jacs.6b11039
 Degree: -

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Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 139 (16) Sequence Number: - Start / End Page: 5640 - 5643 Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870