小柯机器人

新加坡南洋理工大学Julien Lescar、美国波士顿大学医学院Rachel Fearn、Junhua Pan等研究人员合作解析了人偏肺病毒聚合酶蛋白复合物的结构。这一研究成果2019年11月7日在线发表于国际学术期刊《自然》。

据研究人员介绍，呼吸道合胞病毒（RSV）和人偏肺病毒（HMPV）在婴儿和老年人中引起严重的呼吸道疾病。目前既没有疫苗也没有有效的抗病毒治疗来控制RSV或HMPV感染。在病毒基因组复制和转录过程中，四聚体磷蛋白P是核蛋白RNA（N-RNA）模板与L蛋白之间的重要衔接蛋白，其具有RNA依赖性RNA聚合酶（RdRp）、GDP多核糖核苷酸转移酶（PRNTase）和帽特异性甲基转移酶（MTases）活性。对于HMPV或其他主要人类病原体（包括麻疹、埃博拉病毒和狂犬病毒），P与L如何相互作用并介导游离形式N以及核糖核蛋白（RNP）相互作用的方式尚不清楚。

研究人员报道了一个冷冻电镜结构，其显示了聚合酶环形结构和HMPVL的盖帽结构域与P四聚体的结合。连接和MTase结构域相对于核心是可移动的。对于RNA合成启动非常重要的活化环已完全缩回，从而在活性位点腔中留出了空间来延长RNA。P与L的N末端区域广泛相互作用，在界面中覆盖了超过4016平方埃的分子表面积。形成P的卷曲螺旋四聚结构域四个螺旋中的两个，以及从这两个螺旋伸出的长C端延伸，像触手一样包裹着L蛋白。四个P原聚体的结构通用性（在其自由状态下大都无序），体现了一个实现P衔接蛋白功能的“伴侣结合折叠”机制。该结构表明，P具有调节L多种功能的潜力，并且应当加快特定抗病毒药物的设计。

附：英文原文

Title: Structure of the human metapneumovirus polymerase phosphoprotein complex

Author: Junhua Pan, Xinlei Qian, Simon Lattmann, Abbas El Sahili, Tiong Han Yeo, Huan Jia, Tessa Cressey, Barbara Ludeke, Sarah Noton, Marian Kalocsay, Rachel Fearns, Julien Lescar

Issue&Volume: 2019-11-07

Abstract: Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elder adults1. Neither a vaccine nor an effective antiviral therapy exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the nucleoprotein-RNA (N-RNA) template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase (PRNTase) and cap-specific methyltransferases (MTases) activities2,3. How P interacts with L and mediates association with the free form of N and with the ribonucleoprotein (RNP) is not clear for HMPV or other prominent human pathogens including measles, Ebola and rabies viruses. Here, we report a cryo-EM reconstruction showing the ring-shaped structure of the polymerase and capping domains of HMPV L, bound with a tetramer of P. The connector and MTase domains are mobile with respect to the core. The putative priming loop important for initiation of RNA synthesis is fully retracted, leaving space in the active-site cavity for RNA elongation. P interacts extensively with the N-terminal region of L, burying more than 4,016 2 of molecular surface area in the interface. Two of the four helices forming the coiled-coil tetramerization domain of P, and long C-terminal extensions projecting from these two helices, wrap around the L protein like tentacles. The structural versatility of the four P protomers, which are largely disordered in their free state, demonstrates an example of a “folding-upon-partner-binding” mechanism for carrying-out P adaptor functions. The structure shows that P has the potential to modulate multiple functions of L and should accelerate the design of specific antiviral drugs.

DOI: 10.1038/s41586-019-1759-1

Source: https://www.nature.com/articles/s41586-019-1759-1

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