Antiviral function of the human MxA protein and its association with the viral nucleocapsid

本研究的目的是确定人MxA蛋白对甲型流感和其他RNA病毒的抗病毒机制。在之前的资助期内，我们解决了全长MxA的三维结构。它是由三个结构域组成的；结合和水解GTP的球状G结构域，服务于分子间相互作用的柄，以及连接这两个结构域的中心束信号元件。这些结构信息与灵长类动物MxA蛋白的生物信息学分析相结合，使我们确定了一个从MxA柄结构域紧凑结构中伸出的环L4作为目标识别位点。在进一步的研究中，我们发现甲型流感病毒的核蛋白是病毒对Mx蛋白抗病毒功能敏感性的主要决定因素。这些结果将成为我们未来项目的基础，旨在了解MxA广泛抗病毒活性的分子基础，确定甲型流感病毒核蛋白中决定Mx敏感性的基序，并确定可能参与MxA抗病毒作用的其他细胞因子。这些发现可能为开发干扰病毒核衣壳功能的新型抗病毒药物提供科学依据。

The aim of this study is to define the antiviral mechanism of the human MxA protein against influenza A and other RNA viruses. In the preceding funding period we solved the three dimensional structure of full-length MxA. It shows a composition of three domains; the globular G domain that binds and hydrolyzes GTP, the stalk that serves intermolecular interactions, and the central bundle signalling element that connects these two domains. This structural information combined with bioinformatics analysis of primate MxA proteins enabled us to identify a loop L4 that projects out of the compact structure of the MxA stalk domain as the target recognition site. In a further study we identified the nucleoprotein of influenza A virus as the main determinant of viral sensitivity towards the antiviral function of Mx proteins. These results will be the basis of our future projects aiming at understanding the molecular basis of the broad antiviral activity of MxA, characterizing the motif in the viral nucleoprotein of influenza A virus that determines Mx sensitivity, and identifying additional cellular factors that might be involved in MxA antiviral action. These insights might provide a scientific basis for the development of novel antiviral agents disturbing the function of viral nucleocapsids.