Structure-Based Design of Prefusion-Stabilized Filovirus Glycoprotein Trimers.,Cell Reports

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Structure-Based Design of Prefusion-Stabilized Filovirus Glycoprotein Trimers.
Cell Reports ( IF 7.5 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.celrep.2020.03.025
Lucy Rutten ₁ , Morgan S A Gilman ₂ , Sven Blokland ₁ , Jarek Juraszek ₁ , Jason S McLellan ₂ , Johannes P M Langedijk ₁

Affiliation

Ebola virus causes severe hemorrhagic fever, often leading to death in humans. The trimeric fusion glycoprotein (GP) is the sole target for neutralizing antibodies and is the major focus of vaccine development. Soluble GP ectodomains are unstable and mostly monomeric when not fused to a heterologous trimerization domain. Here, we report structure-based designs of Ebola and Marburg GP trimers based on a stabilizing mutation in the hinge loop in refolding region 1 and substitution of a partially buried charge at the interface of the GP1 and GP2 subunits. The combined substitutions (T577P and K588F) substantially increased trimer expression for Ebola GP proteins. We determined the crystal structure of stabilized GP from the Makona Zaire ebolavirus strain without a trimerization domain or complexed ligand. The structure reveals that the stabilized GP adopts the same trimeric prefusion conformation, provides insight into triggering of GP conformational changes, and should inform future filovirus vaccine development.

中文翻译：

预融合稳定的丝状病毒糖蛋白三聚体的基于结构的设计。

埃博拉病毒引起严重的出血热，常常导致人类死亡。三聚体融合糖蛋白（GP）是中和抗体的唯一目标，并且是疫苗开发的主要重点。可溶性GP胞外域是不稳定的，并且当不融合至异源三聚域时大部分是单体的。在这里，我们报告基于埃博拉病毒和Marburg GP三聚体的基于结构的设计，该结构基于重折叠区域1的铰链环中的稳定突变以及GP1和GP2亚基界面处的部分掩埋电荷的替代。组合的替代物（T577P和K588F）大大增加了埃博拉GP蛋白的三聚体表达。我们确定了无三聚域或复合配体的Makona Zaire埃博拉病毒株的稳定GP的晶体结构。

更新日期：2020-03-31

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