Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation.
Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation.
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非平衡炼金模拟研究LOXL2中二硫键的氧化还原电位
DOI：
10.3389/fchem.2021.797036
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发表时间：
2021
影响因子：
5.5
通讯作者：
Dong G
中科院分区：
文献类型：
--
作者：
Lin L;Zou H;Li W;Xu LY;Li EM;Dong G
赖氨酰氧化酶样2（Lysyl oxidase-like 2，LOXL 2）是一种金属酶，催化赖氨酸的ε-氨基氧化脱氨。发现LOXL 2是癌细胞转移和侵袭的促进剂。二硫键是LOXL 2的重要组成部分，对蛋白质结构起稳定作用或对调节蛋白质生物活性起功能作用。二硫键的氧化还原电位是决定二硫键功能作用的重要性质之一。在这项研究中，我们已经计算了所有的二硫键的还原电位LOXL 2的非平衡炼金模拟。我们的研究结果表明，17个二硫键中有7个具有介于−182和−298 mV之间的高氧化还原电位，并且可能具有功能性作用，即，催化结构域中的Cys 573-Cys 625、Cys 579-Cys 695、Cys 657-Cys 673和Cys 663-Cys 685，清道夫受体富半胱氨酸（SRCR）结构域中的Cys 351-Cys 414、Cys 464-Cys 530和Cys 477-Cys 543。Cys 351-Cys 414的二硫键可能发挥变构作用，影响癌细胞的转移和侵袭。其他功能键具有与酶活性相关的催化作用。其余的二硫键预计发挥结构作用。我们的研究为LOXL 2中二硫键的分类提供了重要的见解，并可用于靶向LOXL 2中半胱氨酸残基的药物设计。
Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes the oxidative deamination ε-amino group of lysine. It is found that LOXL2 is a promotor for the metastasis and invasion of cancer cells. Disulfide bonds are important components in LOXL2, and they play a stabilizing role for protein structure or a functional role for regulating protein bioactivity. The redox potential of disulfide bond is one important property to determine the functional role of disulfide bond. In this study, we have calculated the reduction potential of all the disulfide bonds in LOXL2 by non-equilibrium alchemical simulations. Our results show that seven of seventeen disulfide bonds have high redox potentials between −182 and −298 mV and could have a functional role, viz., Cys573–Cys625, Cys579–Cys695, Cys657–Cys673, and Cys663–Cys685 in the catalytic domain, Cys351–Cys414, Cys464–Cys530, and Cys477–Cys543 in the scavenger receptor cysteine-rich (SRCR) domains. The disulfide bond of Cys351–Cys414 is predicted to play an allosteric function role, which could affect the metastasis and invasion of cancer cells. Other functional bonds have a catalytic role related to enzyme activity. The rest of disulfide bonds are predicted to play a structural role. Our study provides an important insight for the classification of disulfide bonds in LOXL2 and can be utilized for the drug design that targets the cysteine residues in LOXL2.