HPV16/18 E6蛋白与小分子抑制剂RITA和姜黄素的结合模式研究  

A Study on Binding Modes of HPV16/18 E6 Proteins with Small Molecule Inhibitors RITA and Curcumin

作　　者：张天一 徐苗 丁欢 田菲菲[1] ZHANG Tian-yi;XU Miao;DING Huan;TIAN Fei-fei(School of Life Science and Engineering,Southwest Jiaotong University,Chengdu 610031,Sichuan,China)

机构地区：[1]西南交通大学生命科学与工程学院

出　　处：《生命科学研究》2019年第5期367-376,共10页Life Science Research

基　　金：国家自然科学基金资助项目(31601066)

摘　　要：持续感染高危型人乳头瘤病毒(human papilloma virus, HPV)会导致宫颈上皮细胞的细胞周期发生变化和免疫逃逸,最终导致宫颈癌。高危型HPV病毒的E6蛋白对抑癌蛋白p53的泛素化降解可被小分子化合物RITA (reactivation of p53 and induction of tumor cell apoptosis)和姜黄素抑制,使HPV阳性细胞被抑制的凋亡功能得以恢复,但这一现象的分子机制尚未得到阐释。本文选择HPV16和HPV18两种高危亚型,采用同源建模、分子对接和分子动力学模拟等方法,对其E6蛋白与RITA和姜黄素的结合模式进行研究。结果显示,在HPV16/18 E6蛋白41~49残基形成的疏水沟槽, RITA和姜黄素具有一致的构象和相似的结合模式,组成疏水沟槽的苯丙氨酸残基和小分子抑制剂的芳环通过疏水作用和π-π相互作用在维持复合物构象中起重要作用。这一结果表明高危型HPV E6蛋白具有作为药物靶点的可行性,为宫颈癌特异性小分子治疗药物的研究和设计提供了理论指导。Sustained infection of high-risk human papilloma virus(HPV) leads to changes in the cell cycle of cervical epithelial cells and immune escape, eventually leading to cervical cancer. The ubiquitination of the tumor suppressor protein p53 by the E6 proteins from high-risk HPVs can be inhibited by the small molecule compounds reactivation of p53 and induction of tumor cell apoptosis(RITA) and curcumin, and the apoptotic function of HPV-positive cells can be restored, but the molecular mechanism of this phenomenon has not yet been elucidated. To analyze the binding modes of high-risk HPV oncogenic protein E6 and small molecule inhibitors RITA and curcumin, and to explore the feasibility of E6 protein as a drug target,the most common high-risk HPV subtypes, HPV16 and HPV18, were studied by homology modeling, molecular docking and molecular dynamics simulation. The results showed that RITA and curcumin had a consis-tent conformation and a similar binding pattern in the hydrophobic groove which is formed by residues 41~49 of the HPV16/18 E6 protein. The phenylalanine residues that make up the hydrophobic groove and the aromatic rings of the two inhibitors played important roles in maintaining the conformation of the complex by hydrophobic interactions and π-π interactions. This research indicated the feasibility of the high-risk HPV E6 protein as a drug target, and may provide theoretical guidance for screening and designing cervical can-cer-specific small molecule drugs.

关 键 词：宫颈癌 小分子抑制剂 分子对接 结合模式 

分 类 号：Q51[生物学—生物化学]