Prion infections cause conformational changes of the cellular prion protein (PrP^C) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrP^C. Expression of a PrP^2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrP^R207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrP^C, but not PrP^2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.

朊病毒感染引起细胞朊病毒蛋白 (PrP ^C ) 的构象变化，并导致进行性神经损伤。在这里，我们显示有毒的朊病毒模拟配体诱导分子内 R208-H140 氢键（'H-latch'），改变 PrP ^C的 α2-α3 和 β2-α2 环的灵活性。^{模拟H-latch 的PrP 2Cys}突变体的表达是组成性毒性的，而不能形成H-latch 的PrP ^R207A突变体赋予对朊病毒感染的抗性。阻止 H-latch 诱导的高亲和力配体抑制了器官型小脑培养物中与朊病毒相关的神经变性。然后我们选择结合野生型 PrP ^C的噬菌体展示配体，但不选择 PrP ^2Cys. 这些粘合剂减少了 H 锁存的构象异构体，并赋予了对朊病毒毒性的保护作用。最后，尽管朊病毒传播不受阻碍，但合理设计用于防止 H-latch 形成的抗体的脑特异性表达延长了感染朊病毒的小鼠的寿命，证实了 H-latch 是朊病毒神经毒性的重要报告者。