The 26 S proteasome - a promising drug target

Wolfgang Baumeister Max Planck Institute of Biochemistry

The proteasome is the executive arm of the ubiquitin-proteasome pathway of protein degradation. It is a key player in the maintenance of cellular proteostasis removing abnormal or misfolded proteins or proteins which are no longer needed. It comprises two subcomplexes the 20S core particle where the proteolytic activity resides and the 19S regulatory particles which prepare substrates for degradation. The latter includes their recognition, the removal of ubiquitin, their unfolding and translocation into the 20S core particle. When the structure of the core particle was solved in 1995 by x-ray crystallography this immediately suggested a way to inhibit its activity, and the inhibitor that was developed in the light of the structure became a very successful drug for the treatment of multiple myelomas.

But more selective drugs, promising to have less severe side effects could be developed targeting sites in the regulatory particle. But its structure remained elusive until recently when it was solved to atomic resolution using integrative approach combining high resolution EM and orthogonal methods. There is a strong interest in the biotech and pharma industry to use this structure for drug development.

Lasker, K., F. Förster, S. Bohn, T. Walzthoeni, E. Villa, P. Unverdorben, F. Beck, R. Aebersold, A. Sali, and W. Baumeister: Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. P. Natl. Acad. Sci 109, 1380-1387 (2012).

Beck, F., P. Unverdorben, S. Bohn, A. Schweitzer, G. Pfeifer, E. Sakata, S. Nickell, J.M. Plitzko, E. Villa, W. Baumeister and F. Förster: Near-atomic resolution structural model of the yeast 26S proteasome. P. Natl. Acad. Sci 109, 14870-14875 (2012).

Wolfgang Baumeister studied biology, chemistry and physics at the Universities of Muenster and Bonn, Germany, and he obtained his Ph.D. from the University of Düsseldorf in 1973. From 1973-1980 he was Research Associate in the Department of Biophysics at the University of Duesseldorf. He held a Heisenberg Fellowship spending time at the Cavendish Laboratory in Cambridge, England. In 1982 he became a Group Leader at the Max-Planck-Institute of Biochemistry in Martinsried, Germany and in 1988 Director and Head of the Department of Structural Biology. He is also an Honorary Professor on the Physics Faculty at the Technical University in Munich.

Wolfgang Baumeister made seminal contributions to our understanding of the structure and function of the cellular machinery of protein degradation, in particular the proteasome. Moreover, he pioneered the development of cryo-electron tomography. His contributions to science were recognized by numerous awards including the Otto Warburg Medal, the Schleiden Medal, the Louis-Jeantet Prize for Medicine, the Stein and Moore Award, the Harvey Prize in Science and Technology and the Ernst Schering Prize. He is a member of several academies including the US National Academy of Sciences and the American Academy of Arts and Sciences.

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