Published 9 July 2011 by Beatrice Lugger

Robert Huber – Lindau Nobel Laureate Meeting 2011

Proteasome and HtrA/DegP Proteases, Structures, Mechanisms, and Drug Design


Within cells or subcellular compartments misfolded and/or short-lived regulatory proteins are degraded by protease machines, cage-forming multi-subunit assemblages, the proteasome and HtrA/DegP. They are essential components in very complex regulatory pathways and interaction networks, the UPS (ubiquitin proteasome system) and the UPR (unfolded protein response), respectively. Their activity is precisely regulated by maturation from inactive precursors and sequestration of their proteolytic active sites within the particles (proteasome) and by activation of latent forms and oligomerization upon signaling by substrate (HtrA/DegP).

Both systems have proven (proteasome) or promise (HtrA/DegP) to be valuable targets for novel therapeutic drugs and antibiotics. The analyses of numerous crystal structures of the proteasome and the HtrA/DegP protein families complexed with ligands in conjunction with functional studies have provided a sound basis of structure-based design and development of many novel chemical entities as potential clinical candidates.


Clausen, T., Kaiser, M., Huber, R. and Ehrmann, M. (2011). HTRA proteases: regulated proteolysis in protein quality control. Nature Reviews Molecular Cell Biology 12,152-162.

Gräwert, M. A., Gallastegui, N., Stein, M., Schmidt, B., Kloetzel, P. M., Huber, R. and Groll, M. (2011). Elucidation of the α-keto-aldehyde binding mechanism: A lead structure motif for proteasome inhibition. Angewandte Chemie Int. Ed. 50, 542-544.

Beatrice Lugger

Beatrice Lugger is a science journalist and science social media specialist with a background as a chemist. She is Scientific Director of the National Institute for Science Communication, NaWik – @BLugger is her twitter handle, Quantensprung her own blog.