Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1
Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1
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DOI：
10.1107/s0907444912037328
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发表时间：
2012-11-01
期刊：
影响因子：
--
通讯作者：
James, Michael N. G.
中科院分区：
文献类型：
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作者：
Baral, Pravas Kumar;Wieland, Barbara;James, Michael N. G.
朊病毒疾病是以细胞朊病毒蛋白PrPc转化为致病性同种型PrPsc为特征的神经退行性疾病。用抗朊病毒单克隆抗体被动免疫可以阻止朊病毒疾病的进展。在此，抗朊病毒单克隆抗体POM 1与人朊病毒蛋白（huPrP（c））复合的Fab片段的晶体结构已被确定为2.4埃分辨率。POM 1的朊病毒表位与据称治疗性抗体片段ICSM 18 Fab与huPrP（c）复合识别的表位非常接近。POM 1 Fab与huPrP（c）形成1：1复合物，测得的Kd为4.5 x 10（-7）M，表明它们之间存在中等强度的结合。已经在三种朊病毒-抗体复合物：POM 1 Fab-huPrP（c）、ICSM 18 Fab-huPrP（c）和VRQ 14 Fab-ovPrP（c）之间进行了结构比较。由ICSM 18 Fab和VRQ 14 Fab识别的朊病毒表位邻近朊病毒糖基化位点，表明可能的空间位阻和/或改变的体内与糖基化朊病毒蛋白的结合模式。然而，huPrP（c）上的两个糖基化位点均位于远离POM 1 Fab结合表位的位置;因此，在该晶体结构中观察到的结合模式和对该抗体测量的结合亲和力最有可能与体内天然朊病毒蛋白的结合模式和亲和力相同。
Prion diseases are neurodegenerative diseases characterized by the conversion of the cellular prion protein PrP c into a pathogenic isoform PrPsc. Passive immunization with antiprion monoclonal antibodies can arrest the progression of prion diseases. Here, the crystal structure of the Fab fragment of an antiprion monoclonal antibody, POM1, in complex with human prion protein (huPrP(c)) has been determined to 2.4 angstrom resolution. The prion epitope of POM1 is in close proximity to the epitope recognized by the purportedly therapeutic antibody fragment ICSM18 Fab in complex with huPrP(c). POM1 Fab forms a 1: 1 complex with huPrP(c) and the measured K-d of 4.5 x 10(-7) M reveals moderately strong binding between them. Structural comparisons have been made among three prion-antibody complexes: POM1 Fab-huPrP(c), ICSM18 Fab-huPrP(c) and VRQ14 Fab-ovPrP(c). The prion epitopes recognized by ICSM18 Fab and VRQ14 Fab are adjacent to a prion glycosylation site, indicating possible steric hindrance and/or an altered binding mode to the glycosylated prion protein in vivo. However, both of the glycosylation sites on huPrP(c) are positioned away from the POM1 Fab binding epitope; thus, the binding mode observed in this crystal structure and the binding affinity measured for this antibody are most likely to be the same as those for the native prion protein in vivo.