title: Structure-Driven Developments of 26S Proteasome Inhibitors.
abstract: The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Most inhibitors, including all molecules approved for clinical use, target the 20S proteolytic core complex; its structure was determined two decades ago. Hitherto, efforts to develop inhibitors targeting the 19S regulatory particle subunits have been less successful. This is, in part, because the molecular architecture of this subcomplex has been, until recently, poorly understood, and high-resolution structures have been available only for a few subunits. In this review, we describe, from a structural perspective, the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome. We highlight the recent progress achieved in structure-based drug-discovery approaches, and we discuss the prospects for further improvement.
authors.affiliation: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; email: baumeist@biochem.mpg.de.
authors.forename: Paweł
authors.initials: P
authors.lastname: Śledź
authors.affiliation: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; email: baumeist@biochem.mpg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumeister
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D059748:Proteolysis / Q000187:drug effects
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: 19S regulatory particle; AAA ATPase; deubiquitylation; structure-based drug design