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| Title | Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. |
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| Journal, issue, pages | Nat Commun, Vol. 8, Page 15578, Year 2017 |
| Publish date | May 25, 2017 |
 Authors | David Haselbach / Jil Schrader / Felix Lambrecht / Fabian Henneberg / Ashwin Chari / Holger Stark /  |
| PubMed 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 ...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 Å 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. |
 External links | Nat Commun / PubMed:28541292 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.8 Å |
| Structure data | |
| Chemicals |  ChemComp-ADP: |
| Source |
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 Keywords |  HYDROLASE / proteasome / oprozomib / ups / drug-binding |
