Targeting trimeric transmembrane domain 5 of oncogenic latent membrane protein 1 using a computationally designed peptide
Targeting trimeric transmembrane domain 5 of oncogenic latent membrane protein 1 using a computationally designed peptide
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使用计算设计的肽靶向致癌潜膜蛋白 1 的三聚体跨膜结构域 5
DOI：
10.1039/c9sc02474c
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发表时间：
2019
期刊：
影响因子：
8.4
通讯作者：
Wang Xiaohui
中科院分区：
文献类型：
--
作者：
Wang Yibo;Peng Yinghua;Zhang Bo;Zhang Xiaozheng;Li Hongyuan;Wilson Andrew J.;Mineev Konstantin S.;Wang Xiaohui
蛋白质-蛋白质相互作用涉及多种生物过程。因此，这些相互作用是药物开发的重要目标。然而，由于缺乏实验确定的结构和有效的方案来探测其功能，针对基于膜的蛋白质-蛋白质相互作用的肽调节剂的设计是一个具有挑战性的目标。在这里，我们采用合理的肽设计和分子动力学模拟来设计一种可插入膜的肽，该肽可破坏致癌性 Epstein-Barr 病毒 (EBV) 潜伏膜蛋白 1 (LMP-1) 第五跨膜结构域 (TMD5) 的强三聚体自缔合。设计的抗TMD5肽与胶束中的TMD5形成1 : 2异三聚体并抑制细菌膜中的TMD5寡聚化。此外，设计的肽基于 EVB 阳性淋巴瘤细胞中的 NF-κB 活性抑制 LMP-1 同三聚化。结果表明，设计的抗 TMD5 肽可能代表着通过抑制 LMP-1 寡聚化来制定抗 EBV 疗法的一个有希望的起点。据我们所知，这是使用设计的肽抑制剂破坏同源三聚体跨膜螺旋的第一个例子。
Protein–protein interactions are involved in diverse biological processes. These interactions are therefore vital targets for drug development. However, the design of peptide modulators targeting membrane-based protein–protein interactions is a challenging goal owing to the lack of experimentally-determined structures and efficient protocols to probe their functions. Here we employed rational peptide design and molecular dynamics simulations to design a membrane-insertable peptide that disrupts the strong trimeric self-association of the fifth transmembrane domain (TMD5) of the oncogenic Epstein–Barr virus (EBV) latent membrane protein-1 (LMP-1). The designed anti-TMD5 peptide formed 1 : 2 heterotrimers with TMD5 in micelles and inhibited TMD5 oligomerization in bacterial membranes. Moreover, the designed peptide inhibited LMP-1 homotrimerization based on NF-κB activity in EVB positive lymphoma cells. The results indicated that the designed anti-TMD5 peptide may represent a promising starting point for elaboration of anti-EBV therapeutics via inhibition of LMP-1 oligomerization. To the best of our knowledge, this represents the first example of disrupting homotrimeric transmembrane helices using a designed peptide inhibitor.