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Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome
Author(s) -
Cui Haissi,
Baur Regina,
Le Chapelain Camille,
Dubiella Christian,
Heinemeyer Wolfgang,
Huber Eva M.,
Groll Michael
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700021
Subject(s) - chemistry , selectivity , electrophile , stereochemistry , peptidomimetic , structure–activity relationship , combinatorial chemistry , biochemistry , in vitro , peptide , catalysis
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.