Crystal structure of the parasite protease inhibitor chagasin in complex with a host target cysteine protease
Crystal structure of the parasite protease inhibitor chagasin in complex with a host target cysteine protease
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DOI：
10.1016/j.jmb.2007.05.005
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发表时间：
2007-08-03
影响因子：
5.6
通讯作者：
Bujacz, Grzegorz
中科院分区：
文献类型：
--
作者：
Ljunggren, Anna;Redzynia, Izabela;Bujacz, Grzegorz
Chagin是一种由克氏锥虫产生的蛋白质，这种寄生虫会导致查加斯病。这种小蛋白属于最近定义的半胱氨酸蛋白酶抑制剂家族。虽然它在大小(110个氨基酸残基)和功能(它们都抑制类木瓜蛋白酶(CL家族))上与众所周知的抑制物如半胱氨酸蛋白酶相似，但它有一个独特的氨基酸序列和结构。我们以1.75埃的分辨率结晶并解决了蔗糖与宿主半胱氨酸蛋白酶L的络合物的结构。由三个环(L2、L4和L6)组成的抑制楔形结构形成了许多负责与酶高亲和力结合(K-I，39 pm)的接触。所有三个环都与催化槽相互作用，中心环L2直接插入催化中心。L4和L6环从两侧拥抱酶分子，并显示出明显不同的蛋白质-蛋白质识别模式。与本研究中也确定的未络合chagagin的1.7埃结构的比较表明，第一结合环(1-4)的构象变化允许延长与酶活性部位裂解的非启动底物口袋的结合，从而提供很大一部分抑制表面。与半胱氨酸蛋白酶抑制不变链p41片段和半胱氨酸蛋白酶抑制p41片段相比，Chagin结合模式大体相似，但在细节上明显不同。Chagagin-cathepsin L复合结构提供了寄生虫蛋白如何抑制宿主酶的详细信息，该酶在宿主防御中可能具有重要作用。组织蛋白酶L和T ruzzi酶CRUZIPIN在结构和功能上的高度相似性为寄生虫的半胱氨酸蛋白酶活性的靶向提供了线索。这些信息将有助于开发合成抑制剂，作为治疗恰加斯病的潜在药物。(C)2007爱思唯尔有限公司。保留所有权利。
Chagasin is a protein produced by Trypanosoma cruzi, the parasite that causes Chagas' disease. This small protein belongs to a recently defined family of cysteine protease inhibitors. Although resembling well-known inhibitors like the cystatins in size (110 amino acid residues) and function (they all inhibit papain-like (Cl family) proteases), it has a unique amino acid sequence and structure. We have crystallized and solved the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 angstrom resolution. An inhibitory wedge composed of three loops (L2, L4, and L6) forms a number of contacts responsible for high-affinity binding (K-i, 39 pM) to the enzyme. All three loops interact with the catalytic groove, with the central loop L2 inserted directly into the catalytic center. Loops L4 and L6 embrace the enzyme molecule from both sides and exhibit distinctly different patterns of protein-protein recognition. Comparison with a 1.7 angstrom structure of uncomplexed chagasin, also determined in this study, demonstrates that a conformational change of the first binding loop (1-4) allows extended binding to the non-primed substrate pockets of the enzyme active site cleft, thereby providing a substantial part of the inhibitory surface. The mode of chagasin binding is generally similar, albeit distinctly different in detail, when compared to those displayed by cystatins and the cysteine protease inhibitory p41 fragment of the invariant chain. The chagasin-cathepsin L complex structure provides details of how the parasite protein inhibits a host enzyme of possible importance in host defense. The high level of structural and functional similarity between cathepsin L and the T cruzi enzyme cruzipain gives clues to how the cysteine protease activity of the parasite can be targeted. This information will aid in the development of synthetic inhibitors for use as potential drugs for the treatment of Chagas disease. (c) 2007 Elsevier Ltd. All rights reserved.