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

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Bravo-Rodriguez,  Kenny
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Mittal,  Sumit
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Sanchez-Garcia,  Elsa
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0000-DFB9-5
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.