Abstract

Recent studies reported the association of the Zika virus (ZIKV) with a stress response receptor on the host cell membrane that facilitates viral entry. This host receptor was the heat shock protein A5 (HSPA5), also termed glucose-regulating protein 78 (GRP78). In this study, structural bioinformatics and molecular dynamics simulations were utilized to suggest the binding site of ZIKV envelope protein during the interaction with cell-surface GRP78. The Pep42 cyclic peptide was used as a profiler, as it was reported earlier, to target GRP78 on the cancer cell membrane selectively. Sequence and structural alignments show that part of the ZIKV envelope protein (C308-C339 region), in addition to its cyclic nature, has somehow sequence and structural similarities to the cyclic Pep42. Three amino acids in the ZIKV envelope were identical to those in the Pep42 peptide. Cyclic peptides dynamics are studied, and its binding to GRP78 is predicted. Protein-protein docking is further performed to explore the binding characteristics of the ZIKV envelope to GRP78. Results revealed that the binding was favorable between ZIKV envelope protein and GRP78. The docking pose revealed the involvement of the substrate-binding domain ß of GRP78 and the domain III of the ZIKV envelope protein in viral recognition for the host-cell.

摘要

最近的研究报告了寨卡病毒 (ZIKV) 与宿主细胞膜上促进病毒进入的应激反应受体的关联。这种宿主受体是热休克蛋白 A5 (HSPA5)，也称为葡萄糖调节蛋白 78 (GRP78)。在这项研究中，利用结构生物信息学和分子动力学模拟来提示 ZIKV 包膜蛋白在与细胞表面 GRP78 相互作用过程中的结合位点。正如之前报道的那样，Pep42 环肽被用作分析器，以选择性地靶向癌细胞膜上的 GRP78。序列和结构比对表明，ZIKV 包膜蛋白的一部分（C308-C339 区域）除了其环状性质外，在某种程度上与环状 Pep42 具有某种序列和结构相似性。ZIKV 包膜中的三个氨基酸与 Pep42 肽中的氨基酸相同。研究了环肽动力学，并预测了其与 GRP78 的结合。进一步进行蛋白质-蛋白质对接以探索 ZIKV 包膜与 GRP78 的结合特征。结果表明，ZIKV 包膜蛋白与 GRP78 的结合良好。对接姿势揭示了 GRP78 的底物结合域 ß 和 ZIKV 包膜蛋白的域 III 参与宿主细胞的病毒识别。