Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei.
Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei.
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DOI：
10.1371/journal.pntd.0000701
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发表时间：
2010-06-08
影响因子：
3.8
通讯作者：
Brinen LS
中科院分区：
文献类型：
--
作者：
Kerr ID;Wu P;Marion-Tsukamaki R;Mackey ZB;Brinen LS
布氏锥虫是人类非洲锥虫病的病原体，非洲锥虫病是撒哈拉以南非洲地区的一种地方性寄生虫病。 TbCatB 和罗得赛因是唯一的 Clan CA 木瓜蛋白酶样半胱氨酸蛋白酶，由寄生虫在感染哺乳动物宿主期间产生，并且与疾病的进展有关。人们相当感兴趣的是探索这两种酶作为有效对抗布氏锥虫的半胱氨酸蛋白酶抑制剂的靶标。我们通过 X 射线晶体学确定了第一个报道的 TbCatB 与组织蛋白酶 B 选择性抑制剂 CA074 复合物的结构。此外，我们还报道了罗得赛因与乙烯基砜 K11002 复合物的结构。我们的 TbCat•CA074 结构的成熟结构域包含组织蛋白酶 B 样酶的独特特征，包括延长的 N 末端，延伸超过预测的成熟切割位点 16 个残基。 N-末端埃德曼测序揭示了比在晶体结构的有序部分中观察到的更长的延伸。 TbCat·CA074 结构证实，作为底物结合位点的重要部分的闭塞环在活性位点裂缝中产生了比哺乳动物组织蛋白酶 B 小分子结构中更大的侧袋。我们的数据进一步强调了闭塞环主链的灵活性增强以及哺乳动物组织蛋白酶 B 酶的结构偏差，这可能会影响活性和抑制剂设计。与 rhodesain•K11002 结构的比较突出了可能影响半胱氨酸蛋白酶抑制剂作为抗锥虫药物的设计的关键差异。蛋白酶普遍存在于所有生命形式中，并催化蛋白质的酶促降解。这些酶调节和协调大量的细胞过程，因此对许多生物体至关重要。虽然丝氨酸蛋白酶在哺乳动物中占主导地位，但寄生生物在其整个生命周期中通常依赖 Clan CA 家族的半胱氨酸蛋白酶。因此，CA 族半胱氨酸蛋白酶被认为是选择性设计药物治疗寄生虫病（例如由布氏锥虫引起的非洲人类锥虫病）的有希望的靶标。动质体（例如锥虫属）的基因组。和利什曼原虫属。编码两种 Clan CA C1 家族半胱氨酸蛋白酶，在 T. brucei 中，这些蛋白酶以 rhodesain 和 TbCatB 为代表。我们已经确定了这两种酶的三维结构，作为我们不断合成更有效的抗锥虫药物的努力的一部分。
Trypanosoma brucei is the etiological agent of Human African Trypanosomiasis, an endemic parasitic disease of sub-Saharan Africa. TbCatB and rhodesain are the sole Clan CA papain-like cysteine proteases produced by the parasite during infection of the mammalian host and are implicated in the progression of disease. Of considerable interest is the exploration of these two enzymes as targets for cysteine protease inhibitors that are effective against T. brucei. We have determined, by X-ray crystallography, the first reported structure of TbCatB in complex with the cathepsin B selective inhibitor CA074. In addition we report the structure of rhodesain in complex with the vinyl-sulfone K11002. The mature domain of our TbCat•CA074 structure contains unique features for a cathepsin B-like enzyme including an elongated N-terminus extending 16 residues past the predicted maturation cleavage site. N-terminal Edman sequencing reveals an even longer extension than is observed amongst the ordered portions of the crystal structure. The TbCat•CA074 structure confirms that the occluding loop, which is an essential part of the substrate-binding site, creates a larger prime side pocket in the active site cleft than is found in mammalian cathepsin B-small molecule structures. Our data further highlight enhanced flexibility in the occluding loop main chain and structural deviations from mammalian cathepsin B enzymes that may affect activity and inhibitor design. Comparisons with the rhodesain•K11002 structure highlight key differences that may impact the design of cysteine protease inhibitors as anti-trypanosomal drugs. Proteases are ubiquitous in all forms of life and catalyze the enzymatic degradation of proteins. These enzymes regulate and coordinate a vast number of cellular processes and are therefore essential to many organisms. While serine proteases dominate in mammals, parasitic organisms commonly rely on cysteine proteases of the Clan CA family throughout their lifecycle. Clan CA cysteine proteases are therefore regarded as promising targets for the selective design of drugs to treat parasitic diseases, such as Human African Trypanosomiasis caused by Trypanosoma brucei. The genomes of kinetoplastids such as Trypanosoma spp. and Leishmania spp. encode two Clan CA C1 family cysteine proteases and in T. brucei these are represented by rhodesain and TbCatB. We have determined three-dimensional structures of these two enzymes as part of our ongoing efforts to synthesize more effective anti-trypanosomal drugs.
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影响因子：
15.8
作者：
Abdulla MH;Lim KC;Sajid M;McKerrow JH;Caffrey CR
通讯作者：
Caffrey CR
影响因子：
4.8
作者：
Illy, C;Quraishi, O;Mort, JS
通讯作者：
Mort, JS
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.7
作者：
Mallari, Jeremy P.;Shelat, Anang;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
影响因子：
3.8
作者：
Abdulla, Maha-Hamadien;O'Brien, Theresa;McKerrow, James H.
通讯作者：
McKerrow, James H.