Structural characterization of the human respiratory syncytial virus fusion protein core
Structural characterization of the human respiratory syncytial virus fusion protein core
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DOI：
10.1073/pnas.260499197
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发表时间：
2000-12-19
影响因子：
11.1
通讯作者：
Kim, PS
中科院分区：
文献类型：
--
作者：
Zhao, X;Singh, M;Kim, PS
人呼吸道合胞病毒（HRSV）是婴儿和幼儿患多种严重呼吸道疾病（包括毛细支气管炎和肺炎）的主要病因。HRSV的F蛋白是一种对病毒进入细胞至关重要的糖蛋白，是疫苗和药物研发的主要靶点。计算机程序LEARN - COIL - VMF预测出HRSV F序列内的两个七肽重复区域。这些区域被认为可形成类似发夹三聚体的结构，与几种有包膜病毒的融合蛋白中的结构相似。发夹结构可能使病毒膜和细胞膜紧密贴近，从而促进膜融合以及随后的病毒进入。在此，我们表明，分别对应于HRSV F蛋白N端和C端片段的七肽重复区域的肽段HR - N和HR - C形成了一种稳定的异二聚体的α - 螺旋三聚体。HRSV的N/C复合物被结晶，其X射线结构在2.3埃分辨率下被确定。正如所预期的，该复合物是一个六螺旋束，其中HR - N肽形成一个三股的中心卷曲螺旋，HR - C肽以反平行的方式堆积在卷曲螺旋表面的疏水凹槽中。HRSV的N/C复合物与其他病毒（包括HIV - 1 gp41）的融合蛋白核心之间存在显著的结构相似性。此外，早期的研究表明，HRSV的HR - C肽像HIV - 1 gp41的C肽一样，可抑制病毒感染。因此，旨在通过阻断发夹形成来抑制病毒进入的药物研发和疫苗开发策略可应用于HRSV的抑制。
Human respiratory syncytial virus (HRSV) is a major cause of a number of severe respiratory diseases, including bronchiolitis and pneumonia, in infants and young children. The HRSV F protein, a glycoprotein essential for viral entry, is a primary target for vaccine and drug development Two heptad-repeat regions within the HRSV F sequence were predicted by the computer program LEARN-COIL-VMF. These regions are thought to form trimer-of-hairpins-like structures, similar to those found in the fusion proteins of several enveloped viruses. The hairpin structure likely brings the viral and cellular membranes into close apposition, thereby facilitating membrane fusion and subsequent viral entry. Here, we show that peptides, denoted HR-N and HR-C, corresponding to the heptad-repeat regions from the N-terminal and C-terminal segments of the HRSV F protein, respectively, form a stable alpha -helical trimer of heteradimers. The HRSV N/C complex was crystallized and its x-ray structure was determined at 2.3-Angstrom resolution. As anticipated, the complex is a six-helix bundle in which the HR-N peptides form a three-stranded, central coiled coil, and the HR-C peptides pack in an antiparallel manner into hydrophobic grooves on the coiled-coil surface. There is remarkable structural similarity between the HRSV N/C complex and the fusion protein core of other viruses, including HIV-1 gp41. In addition, earlier work has shown that HRSV HR-C peptides, like the HIV-1 gp41 C peptides, inhibit viral infection. Thus, drug discovery and vaccine development strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of HRSV.