5m32 | pdb_00005m32
Human 26S proteasome in complex with Oprozomib
Structural highlights
FunctionPSA7_HUMAN The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Plays an important role in the regulation of cell proliferation or cell cycle control, transcriptional regulation, immune and stress response, cell differentiation, and apoptosis. Interacts with some important proteins involved in transcription factor regulation, cell cycle transition, viral replication and even tumor initiation and progression. Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 A 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. 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 Nat Commun. 2017 May 25;8:15578. doi: 10.1038/ncomms15578. PMID:28541292[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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