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

Author

Listed:
  • David Haselbach

    (Max-Planck Institute for Biophysical Chemistry)

  • Jil Schrader

    (Max-Planck Institute for Biophysical Chemistry)

  • Felix Lambrecht

    (Max-Planck Institute for Biophysical Chemistry)

  • Fabian Henneberg

    (Max-Planck Institute for Biophysical Chemistry)

  • Ashwin Chari

    (Max-Planck Institute for Biophysical Chemistry)

  • Holger Stark

    (Max-Planck Institute for Biophysical Chemistry)

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 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.

Suggested Citation

  • David Haselbach & Jil Schrader & Felix Lambrecht & Fabian Henneberg & Ashwin Chari & Holger Stark, 2017. "Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs," Nature Communications, Nature, vol. 8(1), pages 1-8, August.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15578
    DOI: 10.1038/ncomms15578
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    Cited by:

    1. Bintao He & Fa Zhang & Chenjie Feng & Jianyi Yang & Xin Gao & Renmin Han, 2024. "Accurate global and local 3D alignment of cryo-EM density maps using local spatial structural features," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Fanindra Kumar Deshmukh & Gili Ben-Nissan & Maya A. Olshina & Maria G. Füzesi-Levi & Caley Polkinghorn & Galina Arkind & Yegor Leushkin & Irit Fainer & Sarel J. Fleishman & Dan Tawfik & Michal Sharon, 2023. "Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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