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  Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.

Haselbach, D., Schrader, J., Lambrecht, F., Henneberg, F., Chari, A., & Stark, H. (2017). Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. Nature Communications, 8: 15578. doi:10.1038/ncomms15578.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-5ADA-C Version Permalink: http://hdl.handle.net/21.11116/0000-0001-263E-0
Genre: Journal Article

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 Creators:
Haselbach, D.1, Author              
Schrader, J.1, Author              
Lambrecht, F.1, Author              
Henneberg, F.1, Author              
Chari, A.1, Author              
Stark, H.1, Author              
Affiliations:
1Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              

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 Abstract: The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 angstrom from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors.

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Language(s): eng - English
 Dates: 2017-05-25
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/ncomms15578
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Title: Nature Communications
Source Genre: Journal
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Pages: 8 Volume / Issue: 8 Sequence Number: 15578 Start / End Page: - Identifier: -