Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate
Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate
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DOI：
10.1111/j.1365-2958.2005.05036.x
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发表时间：
2006-03-01
影响因子：
3.6
通讯作者：
Li, HL
中科院分区：
文献类型：
--
作者：
Hu, GQ;Lin, G;Li, HL
结核分枝杆菌（Mycobacterium tuberculosis，Mtb）具有显著的抵抗人类巨噬细胞杀伤的能力。750 kDa的蛋白酶体，在大多数真细菌除了放线菌，似乎有助于结核分枝杆菌的耐药性。Mtb蛋白酶体在3.0埃分辨率下的晶体结构揭示了具有真核蛋白酶体的不同β 1、β 2和β 5底物结合位点的复合特征的底物结合口袋，这解释了Mtb蛋白酶体对伴随文章[Lin et al.（2006），Mol Microbiol doi：10.1111/j.1365-2958.2005.05035.x]中描述的寡肽的广泛特异性。由于α-亚基N-末端残基的部分无序，圆柱形蛋白酶体末端的底物入口在晶体结构中出现开放。然而，核心颗粒的冷冻电子显微镜显示封闭端，与负染色电子显微镜中观察到的密度一致，这取决于同伴文章中α亚基的N-末端octapetides的存在，表明Mtb蛋白酶体具有门控结构。我们首次确定了二肽基硼酸酯N-（4-吗啉）羰基-β-（1-萘基）-L-丙氨酸-L-亮氨酸硼酸（MLN-273）（抗骨髓瘤药物硼替佐米的类似物）的蛋白酶体抑制机制。该结构改善了设计Mtb特异性蛋白酶体抑制剂作为结核病化疗的新方法的前景。
Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by human macrophages. The 750 kDa proteasome, not available in most eubacteria except Actinomycetes, appears to contribute to Mtb's resistance. The crystal structure of the Mtb proteasome at 3.0 angstrom resolution reveals a substrate-binding pocket with composite features of the distinct beta 1, beta 2 and beta 5 substrate binding sites of eukaryotic proteasomes, accounting for the broad specificity of the Mtb proteasome towards oligopeptides described in the companion article [Lin et al. (2006), Mol Microbiol doi:10.1111/j.1365-2958.2005.05035.x]. The substrate entrance at the end of the cylindrical proteasome appears open in the crystal structure due to partial disorder of the alpha-subunit N-terminal residues. However, cryo-electron microscopy of the core particle reveals a closed end, compatible with the density observed in negative-staining electron microscopy that depended on the presence of the N-terminal octapetides of the alpha-subunits in the companion article, suggesting that the Mtb proteasome has a gated structure. We determine for the first time the proteasomal inhibition mechanism of the dipeptidyl boronate N-(4-morpholine)carbonyl-beta-(1-naphthyl)-L-alanine- L-leucine boronic acid (MLN-273), an analogue of the antimyeloma drug bortezomib. The structure improves prospects for designing Mtb-specific proteasomal inhibitors as a novel approach to chemotherapy of tuberculosis.