Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R.
Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R.
复制标题
DOI：
10.1074/jbc.m603275200
复制
发表时间：
2006-11-10
期刊：
影响因子：
--
通讯作者：
Liddington RC
中科院分区：
文献类型：
--
作者：
Hwang WC;Lin Y;Santelli E;Sui J;Jaroszewski L;Stec B;Farzan M;Marasco WA;Liddington RC
严重急性呼吸综合征（SARS）是2003年引起大流行的一种新型传染病。SARS的病原体是一种新型冠状病毒（SARS-CoV）。冠状病毒表面刺突蛋白S是一种I型跨膜糖蛋白，通过细胞表面受体血管紧张素转换酶2（ACE 2）介导初始宿主结合，以及随后进入细胞所需的膜融合事件。在这里，我们报告的晶体结构的S1受体结合结构域（RBD）与中和抗体，80 R，在2.3倍分辨率的复合物，以及在2.2倍分辨率的未复合的S1 RBD的结构。我们表明，S1 RBD上的80 R结合表位与ACE 2结合位点非常紧密地重叠，为抗体的强结合和广泛中和能力提供了理论基础。我们提供了一个结构上的差异效应的某些突变的刺突蛋白对80 R与ACE 2结合，包括逃逸突变体，这将有助于设计的免疫治疗，以治疗未来的SARS爆发。我们进一步表明，S1的RBD通过广泛的界面形成二聚体，该界面在受体和抗体结合的晶体结构中被破坏，并且我们提出了二聚体在病毒稳定性和感染性中的作用。
Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease that caused pandemic spread in 2003. The etiological agent of SARS is a novel coronavirus (SARS-CoV). The coronaviral surface spike protein S is a type I transmembrane glycoprotein that mediates initial host binding via the cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the subsequent membrane fusion events required for cell entry. Here we report the crystal structure of the S1 receptor binding domain (RBD) in complex with a neutralizing antibody, 80R, at 2.3 Å resolution, as well as the structure of the uncomplexed S1 RBD at 2.2 Å resolution. We show that the 80R-binding epitope on the S1 RBD overlaps very closely with the ACE2-binding site, providing a rationale for the strong binding and broad neutralizing ability of the antibody. We provide a structural basis for the differential effects of certain mutations in the spike protein on 80R versus ACE2 binding, including escape mutants, which should facilitate the design of immunotherapeutics to treat a future SARS outbreak. We further show that the RBD of S1 forms dimers via an extensive interface that is disrupted in receptor- and antibody-bound crystal structures, and we propose a role for the dimer in virus stability and infectivity.