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  Structure-Driven Developments of 26S Proteasome Inhibitors

Sledz, P., & Baumeister, W. (2016). Structure-Driven Developments of 26S Proteasome Inhibitors. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 56, 191-209. doi:10.1146/annurev-pharmtox-010814-124727.

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 Creators:
Sledz, Pawel1, Author              
Baumeister, Wolfgang1, Author              
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: CHYMOTRYPSIN-LIKE ACTIVITY; MULTICATALYTIC PROTEINASE COMPLEX; SENSITIVE NEUTRAL ENDOPEPTIDASE; LACTACYSTIN BETA-LACTONE; TRYPSIN-LIKE SITES; NF-KAPPA-B; 20S PROTEASOME; DRUG DESIGN; REGULATORY PARTICLE; CRYSTAL-STRUCTURE19S regulatory particle; structure-based drug design; AAA ATPase; deubiquitylation;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 19
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
  Alternative Title : Annu. Rev. Pharmacol. Toxicol.
Source Genre: Journal
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Publ. Info: 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA : ANNUAL REVIEWS
Pages: - Volume / Issue: 56 Sequence Number: - Start / End Page: 191 - 209 Identifier: ISSN: 0362-1642
ISBN: 978-0-8243-0456-0