title: Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome.
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.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Haissi
authors.identifier: 0000-0003-3358-8958
authors.initials: H
authors.lastname: Cui
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Baur
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Camille
authors.identifier: 0000-0001-5347-6035
authors.initials: C
authors.lastname: Le Chapelain
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Christian
authors.identifier: 0000-0001-5801-2053
authors.initials: C
authors.lastname: Dubiella
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Heinemeyer
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Eva M
authors.identifier: 0000-0001-8018-7204
authors.initials: EM
authors.lastname: Huber
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-1660-340X
authors.initials: M
authors.lastname: Groll
mesh_terms: D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry*
chemical_list: D007155:Immunologic Factors; D009842:Oligopeptides; C542291:PR-957; D010455:Peptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: crystallography; drug design; immunoproteasome; inhibitors; specificity