1. Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome
- Author
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Eva M. Huber, Michael Groll, Haissi Cui, Regina Baur, Camille Le Chapelain, Christian Dubiella, and Wolfgang Heinemeyer
- Subjects
Models, Molecular ,0301 basic medicine ,Proteasome Endopeptidase Complex ,Molecular Structure ,Yeast Model ,Stereochemistry ,Organic Chemistry ,Selective inhibition ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Electrophile ,Humans ,Immunologic Factors ,Molecular Medicine ,Peptides ,Thiazole ,Oligopeptides ,Proteasome Inhibitors ,Molecular Biology ,Lead compound - 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 non-peptidic scaffold with the absence of an electrophile has been reported in a patent. Herein, we describe the mode of action of the lead compound 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. Distinctive interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity.
- Published
- 2017