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首页> 外文期刊>Biochemistry >Inhibition of a cathepsin L-like cysteine protease by a chimeric propeptide-derived inhibitor
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Inhibition of a cathepsin L-like cysteine protease by a chimeric propeptide-derived inhibitor

机译：嵌合前肽衍生的抑制剂对组织蛋白酶L样半胱氨酸蛋白酶的抑制

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摘要

Like other papain-related cathepsins, congopain from Trypanosoma congolense is synthesized as a zymogen. We have previously identified a proregion-derived peptide (Pcp27), acting as a weak and reversible inhibitor of congopain. Pcp27 contains a 5-mer YHNGA motif, which is essential for selectivity in the inhibition of its mature form [Lalmanach, G., Lecaille, F., Chagas, J. R., Authie, E., Scharfstein, J., Juliano, M. A., and Gauthier, F. (1998) J. Biol. Chem. 273, 25112-25116]. In the work presented here, a homology model of procongopain was generated and subsequently used to model a chimeric 50-mer peptide (called H3-Pcp27) corresponding to the covalent linkage of an unrelated peptide (H3 helix from Antennapedia) to Pcp27. Molecular simulations suggested that H3-Pcp27 (pI = 9.99) maintains an N-terminal helical conformation, and establishes more complementary electrostatic interactions (E-coul = -25.77 kcal/mol) than 16N-Pcp27, the 34-mer Pcp27 sequence plus the 16 native residues upstream from the proregion (E-coul = 0.20 kcal/mol), with the acid catalytic domain (pI = 5.2) of the mature enzyme. In silico results correlated with the significant improvement of congopain inhibition by H3-Pcp27 (K; = 24 nM), compared to 16N-Pep27 (K-i = 1 mu M). In addition, virtual alanine scanning of H3 and 16N identified the residues contributing most to binding affinity. Both peptides did not inhibit human cathepsins B and L. In conclusion, these data support the notion that the positively charged H3 helix favors binding, without modifying the selectivity of Pcp27 for congopain.
机译：像其他木瓜蛋白酶相关的组织蛋白酶一样，锥虫锥虫的刚果素也被合成为酶原。我们先前已经确定了前区衍生肽（Pcp27），可作为刚果民主共和国的弱而可逆的抑制剂。 Pcp27包含5个单体的YHNGA基序，这对于抑制其成熟形式的选择性至关重要[Lalmanach，G.，Lecaille，F.，Chagas，JR，Authie，E.，Scharfstein，J.，Juliano，MA，和Gauthier，F。（1998）生物化学杂志。化学273，25112-25116]。在此处介绍的工作中，生成了procongopain的同源性模型，随后将其用于建模与不相关肽（来自Anantennapedia的H3螺旋）与Pcp27的共价连接相对应的嵌合50-mer肽（称为H3-Pcp27）。分子模拟表明，H3-Pcp27（pI = 9.99）保持N末端螺旋构象，并建立比16N-Pcp27、34-mer Pcp27序列加16N-Pcp27互补的互补静电相互作用（E-coul = -25.77 kcal / mol）。前区上游的16个天然残基（E-coul = 0.20 kcal / mol），带有成熟酶的酸性催化结构域（pI = 5.2）。与16N-Pep27（K-1 = 1μM）相比，计算机分析结果与H3-Pcp27（K; = 24 nM）对刚果蛋白酶抑制的显着改善有关。此外，对H3和16N进行虚拟丙氨酸扫描可确定对结合亲和力贡献最大的残基。两种肽均不抑制人组织蛋白酶B和L。总而言之，这些数据支持以下观点：带正电荷的H3螺旋有利于结合，而不会改变Pcp27对刚果的选择性。

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