Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome

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...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2017-03, Vol.18 (6), p.523-526
Main Authors: Cui, Haissi, Baur, Regina, Le Chapelain, Camille, Dubiella, Christian, Heinemeyer, Wolfgang, Huber, Eva M., Groll, Michael
Format: Article
Language:English
Subjects:
crystallography
drug design
Humans
Immunologic Factors - chemistry
immunoproteasome
inhibitors
Models, Molecular
Molecular Structure
Oligopeptides - chemistry
Peptides - chemistry
Proteasome Endopeptidase Complex - chemistry
Proteasome Endopeptidase Complex - drug effects
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors - chemistry
specificity
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Summary: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. 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.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201700021