Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome. (22nd February 2017)

• Record Type: Journal Article
• Authors: Cui, Haissi; Baur, Regina; Le Chapelain, Camille; Dubiella, Christian; Heinemeyer, Wolfgang; Huber, Eva M.; Groll, Michael
• Is Part Of: Chembiochem. Volume 18:Number 6(2017)
• Page Start: 523
• Page End: 526
• Publication Date: 2017-02-22
• Subjects: crystallography -- drug design -- immunoproteasome -- inhibitors -- specificity; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700021
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Selective inhibition of the immunoproteasome is a promising approach towards the development of immunomodulatory drugs. Recently, a class of substituted thiazole compounds that combine a nonpeptidic scaffold with the absence of an electrophile was reported in a patent. Here, we investigated the mode of action of the lead compound by using a sophisticated chimeric yeast model of the human immunoproteasome for structural studies. The inhibitor adopts a unique orientation perpendicular to the β5i substrate‐binding channel. Distinct interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity. Abstract : Better off‐site : The binding mechanism of an industrially patented, non‐covalent, nonpeptidic, subunit‐specific immunoproteasome inhibitor was studied. This revealed distinct interactions that account for its isotype‐ and species‐selectivity towards the human immunoproteasome.