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

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 an

SUBMITTER: Haselbach D 

PROVIDER: S-EPMC5458511 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature