Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity
Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity
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DOI：
10.1016/j.cell.2011.12.030
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发表时间：
2012-02-17
期刊：
影响因子：
64.5
通讯作者：
Groll, Michael
中科院分区：
文献类型：
--
作者：
Huber, Eva M.;Basler, Michael;Groll, Michael
组成性蛋白酶体和免疫蛋白酶体通过携带不同的催化活性亚基组来形成由主要组织相容性复合物I类（MHC-I）分子呈递的肽库。在这里，我们以2.9埃的分辨率展示了在存在和不存在环氧酮抑制剂PR-957（ONX 0914）的情况下小鼠组成型蛋白酶体和免疫蛋白酶体的晶体结构。基于我们的X射线数据，我们提出了一个独特的催化功能的免疫蛋白酶体亚基β 5i/LMP 7。无配体和配体结合的蛋白酶体的比较揭示了β 5c/X而不是β 5i的S1口袋中的构象变化，从而解释了PR-957对β 5i的选择性。酵母蛋白酶体的时间分辨结构：PR-957复合物表明，配体对接到活性位点只发生通过反应头基和P1侧链。总之，我们的研究结果支持对免疫蛋白酶体具有选择性的抑制性先导结构的结构导向设计，这些免疫蛋白酶体与细胞因子产生和疾病（如癌症和自身免疫性疾病）有关。
Constitutive proteasomes and immunoproteasomes shape the peptide repertoire presented by major histocompatibility complex class I (MHC-I) molecules by harboring different sets of catalytically active subunits. Here, we present the crystal structures of constitutive proteasomes and immunoproteasomes from mouse in the presence and absence of the epoxyketone inhibitor PR-957 (ONX 0914) at 2.9 angstrom resolution. Based on our X-ray data, we propose a unique catalytic feature for the immunoproteasome subunit beta 5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of beta 5c/X but not beta 5i, thereby explaining the selectivity of PR-957 for beta 5i. Time-resolved structures of yeast proteasome: PR-957 complexes indicate that ligand docking to the active site occurs only via the reactive head group and the P1 side chain. Together, our results support structure-guided design of inhibitory lead structures selective for immunoproteasomes that are linked to cytokine production and diseases like cancer and autoimmune disorders.