Prion disease is caused by the misfolding of the cellular prion protein, PrP^C, into a self-templating conformer, PrP^Sc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrP^C and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrP^Sc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrP^C with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrP^C. Thus, it is essential to expand our structural knowledge about PrP^C as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrP^C that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process.

朊病毒病是由细胞朊病毒蛋白 PrP ^C错误折叠成自模板构象异构体 PrP ^Sc引起的。核磁共振 (NMR) 和 X 射线晶体学揭示了 PrP ^C球状结构域的 3D 结构，以及其通过因结构域交换或两个单体的非共价结合而形成的链间二硫键二聚化的可能性。相反，PrP ^Sc由与不同模式的神经毒性相关的复杂且异质的构象和四元排列组成。靶向 PrP ^C具有稳定其球状结构域天然构象的分子成为开发抗朊病毒疗法的有前途的方法。这种方法的优点之一是对 PrP ^C采用基于结构的药物发现方法。^{因此，有必要尽可能地扩展我们对 PrP C}的结构知识，以帮助此类药物发现工作。在这项工作中，我们报告了人类 PrP ^C球状结构域的晶体结构，该结构显示了一种新型二聚体形式和一种新型寡聚排列。我们使用分子动力学模拟来探索其结构动力学和稳定性，并讨论这些新的四元结构对转化过程的潜在影响。