Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome
Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome
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DOI：
10.1002/cbic.201700021
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发表时间：
2017-03-16
期刊：
影响因子：
3.2
通讯作者：
Groll, Michael
中科院分区：
文献类型：
--
作者：
Cui, Haissi;Baur, Regina;Groll, Michael
免疫蛋白酶体的选择性抑制是开发免疫调节药物的一种有前途的方法。最近，在一项专利中报道了一类取代的噻唑化合物，其将非肽支架与不存在亲电试剂相结合，联合收割机。在这里，我们通过使用复杂的人类免疫蛋白酶体嵌合酵母模型进行结构研究，研究了先导化合物的作用方式。该抑制剂采用垂直于5i底物结合通道的独特取向。抑制剂和人免疫蛋白酶体的亚袋之间的独特相互作用解释了其同种型选择性。
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 5i substrate-binding channel. Distinct interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity.