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Journal Article

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

MPS-Authors
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Haselbach,  D.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Schrader,  J.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Lambrecht,  F.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Henneberg,  F.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Chari,  A.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Stark,  H.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Fulltext (public)

2451079.pdf
(Publisher version), 3MB

Supplementary Material (public)

2451079_Suppl_1.pdf
(Supplementary material), 5MB

2451079_Suppl_2.avi
(Supplementary material), 23MB

2451079_Suppl_3.mov
(Supplementary material), 10MB

2451079_Suppl_4.mov
(Supplementary material), 5MB

Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002D-5ADA-C
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.