The High-Affinity Chymotrypsin Inhibitor Eglin C Poorly Inhibits Human Chymotrypsin-Like Protease: Gln192 and Lys218 Are Key Determinants.

IF 3.2 4区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-01 Epub Date: 2024-09-20 DOI:10.1002/prot.26750

Bálint Zoltán Németh, Bence Kiss, Miklós Sahin-Tóth, Csaba Magyar, Gábor Pál

引用次数: 0

Abstract

Eglin C, a small protein from the medicinal leech, has been long considered a general high-affinity inhibitor of chymotrypsins and elastases. Here, we demonstrate that eglin C inhibits human chymotrypsin-like protease (CTRL) weaker by several orders of magnitude than other chymotrypsins. In order to identify the underlying structural aspects of this unique deviation, we performed comparative molecular dynamics simulations on experimental and AlphaFold model structures of bovine CTRA and human CTRL. Our results indicate that in CTRL, the primary determinants of the observed weak inhibition are amino-acid positions 192 and 218 (using conventional chymotrypsin numbering), which participate in shaping the S1 substrate-binding pocket and thereby affect the stability of the protease-inhibitor complexes.

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高亲和力糜蛋白酶抑制剂 Eglin C 对人类糜蛋白酶样蛋白酶的抑制效果很差：Gln192和Lys218是关键的决定因素

Eglin C 是一种来自药用水蛭的小蛋白，长期以来一直被认为是糜蛋白酶和弹性蛋白酶的通用高亲和力抑制剂。在这里，我们证明了 Eglin C 对人类糜蛋白酶样蛋白酶（CTRL）的抑制作用比其他糜蛋白酶弱几个数量级。为了确定这种独特偏差的潜在结构方面，我们对牛 CTRA 和人 CTRL 的实验结构和 AlphaFold 模型结构进行了比较分子动力学模拟。我们的结果表明，在 CTRL 中，所观察到的微弱抑制作用的主要决定因素是氨基酸位置 192 和 218（使用传统的糜蛋白酶编号），它们参与形成 S1 底物结合口袋，从而影响蛋白酶-抑制剂复合物的稳定性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学

CiteScore

5.90

自引率

3.40%

发文量

172

审稿时长

3 months

期刊介绍： PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.