Inhibition of huntingtin exon-1 aggregation by the molecular tweezer CLR01

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Item Type:	Article
Title:	Inhibition of huntingtin exon-1 aggregation by the molecular tweezer CLR01
Creators Name:	Vöpel, T., Bravo-Rodriguez, K., Mittal, S., Vachharajani, S., Gnutt, D., Sharma, A., Steinhof, A., Fatoba, O., Ellrichmann, G., Nshanian, M., Heid, C., Loo, J.A., Klärner, F.-G., Schrader, T., Bitan, G., Wanker, E.E., Ebbinghaus, S. and Sanchez-Garcia, E.
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 (htt(e1)). Above a threshold of 37 glutamine residues, htt(e1) starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt(e1) (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt(e1). 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 htt(e1) monomer and inhibits htt(e1) aggregation, underpinning the key role of N17 in modulating htt(e1) toxicity.
Keywords:	Bridged-Ring Compounds, Exons, Huntingtin Protein, Hydrophobic and Hydrophilic Interactions, Molecular Dynamics Simulation, Molecular Structure, Organophosphates, Protein Aggregates
Source:	Journal of the American Chemical Society
ISSN:	0002-7863
Publisher:	American Chemical Society
Volume:	139
Number:	16
Page Range:	5640-5643
Date:	26 April 2017
Official Publication:	https://doi.org/10.1021/jacs.6b11039
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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