Cui Haissi, Baur Regina, Le Chapelain Camille, Dubiella Christian, Heinemeyer Wolfgang, Huber Eva M, Groll Michael
Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748, Garching, Germany.
Chembiochem. 2017 Mar 16;18(6):523-526. doi: 10.1002/cbic.201700021. Epub 2017 Feb 22.
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.
选择性抑制免疫蛋白酶体是开发免疫调节药物的一种有前景的方法。最近，一项专利报道了一类将非肽支架与无亲电试剂相结合的取代噻唑化合物。在此，我们通过使用一种复杂的人免疫蛋白酶体嵌合酵母模型进行结构研究，来探究先导化合物的作用模式。该抑制剂采取垂直于β5i底物结合通道的独特取向。抑制剂与人免疫蛋白酶体亚口袋之间的独特相互作用解释了其同型选择性。
