Novel quaternary structures of the human prion protein globular domain.
Novel quaternary structures of the human prion protein globular domain.
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DOI：
10.1016/j.biochi.2021.09.005
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发表时间：
2021-12
期刊：
影响因子：
3.9
通讯作者：
Nonato MC
中科院分区：
文献类型：
--
作者：
Bortot LO;Rangel VL;Pavlovici FA;El Omari K;Wagner A;Brandao-Neto J;Talon R;von Delft F;Reidenbach AG;Vallabh SM;Minikel EV;Schreiber S;Nonato MC
朊病毒病是由细胞朊病毒蛋白PrPC错误折叠成自模板构象异构体PrPSc引起的。核磁共振（NMR）和X射线晶体学揭示了PrPC球状结构域的3D结构，以及其通过结构域交换或两个单体非共价结合形成的链间二硫键进行二聚化的可能性。相反，PrPSc是由一个复杂的和异构的合奏定义不清的构象和四元安排，与不同的模式的神经毒性。用稳定其球状结构域的天然构象的分子靶向PrPC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将基于结构的药物发现方法应用于PrPC。因此，有必要尽可能地扩大我们对PrPC的结构知识，以帮助这种药物发现工作。在这项工作中，我们报告了一个晶体结构的球状域的人PrPC，显示了一种新的二聚体形式和一种新的寡聚体的安排。我们使用分子动力学模拟来探索其结构动力学和稳定性，并讨论这些新的四级结构的转换过程中的潜在影响。
Prion disease is caused by the misfolding of the cellular prion protein, PrPC, into a self-templating conformer, PrPSc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrPC 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, PrPSc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrPC 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 PrPC. Thus, it is essential to expand our structural knowledge about PrPC as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrPC 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.
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DOI：
10.3390/pathogens7010027
发表时间：
2018-03-07
期刊：
Pathogens (Basel, Switzerland)
影响因子：
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作者：
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