Crystal structure of human prion protein bound to a therapeutic antibody
Crystal structure of human prion protein bound to a therapeutic antibody
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DOI：
10.1073/pnas.0809170106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Collinge, J.
中科院分区：
文献类型：
--
作者：
Antonyuk, S. V.;Trevitt, C. R.;Collinge, J.
朊病毒感染的特征在于宿主细胞朊病毒蛋白（PrPC）转化为疾病相关的构象异构体（PrPSc），并且可以通过抗PrP单克隆抗体的被动免疫在体内被阻止。在这里，我们表明，抗体治愈朊病毒感染细胞的能力与其对PrPC而不是PrPSc的结合亲和力相关。我们通过确定与单克隆抗体ICSM 18的Fab片段结合的人PrP的晶体结构，在分子水平上可视化了这种相互作用，所述单克隆抗体ICSM 18具有对PrPC的最高亲和力和体外和体内的最高治疗效力。在该晶体结构中，观察到人PrP处于其天然PrPC构象。晶体结构中相邻PrP分子之间的相互作用由位置129处残基之间的紧密同型接触介导，导致形成4链分子间β折叠。该残基在介导蛋白质-蛋白质接触中的重要性可以解释由人类朊病毒病中的多态性残基129确定的遗传易感性和朊病毒株选择，这是已知的任何人类疾病中最强的常见易感性多态性之一。
Prion infection is characterized by the conversion of host cellular prion protein (PrPC) into disease-related conformers (PrPSc) and can be arrested in vivo by passive immunization with anti-PrP monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrPC rather than PrPSc. We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrPC and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrPC conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular beta-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.