Impact of tyrosine nitration at positions Tyr307 and Tyr335 on structural dynamics of Lipoprotein-associated phospholipase A2-A therapeutically important cardiovascular biomarker for atherosclerosis
Impact of tyrosine nitration at positions Tyr307 and Tyr335 on structural dynamics of Lipoprotein-associated phospholipase A2-A therapeutically important cardiovascular biomarker for atherosclerosis
复制标题
DOI：
10.1016/j.ijbiomac.2017.10.068
复制
发表时间：
2018-02-01
影响因子：
8.2
通讯作者：
Bhattacharjee, Atanu
中科院分区：
文献类型：
--
作者：
Gurung, Arun Bahadur;Bhattacharjee, Atanu
蛋白质酪氨酸硝化（PTN）是一种翻译后事件，其导致3-硝基酪氨酸（3-NT）的产生。高水平的3-NT被报道在几种人类疾病中，如帕金森病、阿尔茨海默病、肌萎缩侧索硬化症和冠状动脉疾病。脂蛋白相关磷脂酶A（2）（Lipoprotein-associated phospholipase A（2），Lp-PLA（2））307和335位的PTN抑制了其酶活性，但其抑制机理在结构水平上还不清楚。本研究是一项计算机模拟奋进了解Lp-PLA（2）中硝化应力诱导的结构变化。分子对接研究显示，由于氢键相互作用模式的差异，底物血小板活化因子（PAF）与硝化形式的Lp-PLA（2）（NT-Tyr 307和NT-Tyr 335）的结合亲和力与野生型相比降低。分子动力学（MD）模拟研究表明，更高的灵活性的硝化形式相比，野生型，定向的催化三联体和减少的分子相互作用的NT-Tyr 307和NT-Tyr 335与其他残基的蛋白质。基本动力学（艾德）进一步证实了Lp-PLA硝化形式的结构灵活性增强（2）。我们的研究结果将有助于理解硝化应激诱导的Lp-PLA（2）抑制的分子机制，这可能进一步有助于设计对PTN具有保护功能的治疗剂。(C)2017爱思唯尔B. V.保留所有权利。
Protein tyrosine nitration (PTN) is a post translational event which results in the generation of 3-Nitrotyrosine (3-NT). High levels of 3-NT were reported in several human diseases such as Parkinson's disease, Alzheimer's disease, amylotrophic lateral sclerosis and coronary artery disease. It was reported that PTN at positions 307 and 335 of Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) curtails its enzymatic activity but the mechanism of inhibition at the structure level is still incomprehensible. The present study is an in silico endeavor to understand nitrative stress induced structural changes in Lp-PLA(2). Molecular docking studies revealed a decreased binding affinity of substrate, Platelet Activating Factor (PAF) with the nitrated forms of Lp-PLA(2) (NT-Tyr307 and NT-Tyr335) compared to the wild type, due to differences in the hydrogen bond interaction patterns. Molecular dynamics (MD) simulation studies suggests higher flexibility of nitrated forms compared to wild type, disorientation of the catalytic triad and decreased molecular interactions of NT-Tyr307 and NT-Tyr335 with other residues of the protein. Essential dynamics (ED) further confirmed the enhanced structural flexibility of nitrated forms of Lp-PLA(2). Our findings would help understand the molecular mechanism of nitrative stress induced inhibition of Lp-PLA(2) which may further assist in designing of therapeutics having protective functions against PTN. (C) 2017 Elsevier B.V. All rights reserved.