Prion or PrPSc is the proteinaceous infectious agent causing prion diseases in various mammalian species. Despite decades of research, the structural basis for PrPSc formation and prion infectivity remains elusive. To understand the role of the hydrophobic region in forming infectious prion at the molecular level, we report X-ray crystal structures of mouse (Mo) prion protein (PrP) (residues 89-230) in complex with a nanobody (Nb484). Using the recombinant prion propagation system, we show that the binding of Nb484 to the hydrophobic region of MoPrP efficiently inhibits the propagation of proteinase K resistant PrPSc and prion infectivity. In addition, when added to cultured mouse brain slices in high concentrations, Nb484 exhibits no neurotoxicity, which is drastically different from other neurotoxic anti-PrP antibodies, suggesting that the Nb484 can be a potential therapeutic agent against prion disease. In summary, our data provides the first structure-function evidence supporting a crucial role of the hydrophobic region of PrP in forming an infectious prion.

中文翻译：

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evidence病毒蛋白疏水区在形成感染性ion病毒中的关键作用的结构证据。

on病毒或PrPSc是蛋白质感染剂，可在多种哺乳动物中引起病毒疾病。尽管进行了数十年的研究，但PrPSc形成和病毒感染性的结构基础仍然难以捉摸。若要了解疏水区域在分子水平上形成感染性ion病毒的作用，我们报告了与纳米抗体（Nb484）形成复合结构的小鼠（Mo）ion病毒蛋白（PrP）（残基89-230）的X射线晶体结构。使用重组病毒繁殖系统，我们表明Nb484与MoPrP疏水区域的结合有效地抑制了蛋白酶K抗性PrPSc的繁殖和病毒的感染性。此外，当将Nb484高浓度添加到培养的小鼠脑切片中时，它不会表现出神经毒性，这与其他具有神经毒性的抗PrP抗体完全不同，提示Nb484可能是对抗病毒疾病的潜在治疗剂。总而言之，我们的数据提供了第一个结构功能证据，支持了PrP疏水区在形成感染性病毒中的关键作用。