Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
Janssen BioPharma, Inc., Janssen Pharmaceutical Companies, South San Francisco, CA 94080, USA.
Cell. 2019 Sep 19;179(1):193-204.e14. doi: 10.1016/j.cell.2019.08.014. Epub 2019 Sep 5.
Numerous interventions are in clinical development for respiratory syncytial virus (RSV) infection, including small molecules that target viral transcription and replication. These processes are catalyzed by a complex comprising the RNA-dependent RNA polymerase (L) and the tetrameric phosphoprotein (P). RSV P recruits multiple proteins to the polymerase complex and, with the exception of its oligomerization domain, is thought to be intrinsically disordered. Despite their critical roles in RSV transcription and replication, structures of L and P have remained elusive. Here, we describe the 3.2-Å cryo-EM structure of RSV L bound to tetrameric P. The structure reveals a striking tentacular arrangement of P, with each of the four monomers adopting a distinct conformation. The structure also rationalizes inhibitor escape mutants and mutations observed in live-attenuated vaccine candidates. These results provide a framework for determining the molecular underpinnings of RSV replication and transcription and should facilitate the design of effective RSV inhibitors.
有许多针对呼吸道合胞病毒 (RSV) 感染的干预措施正在临床开发中，包括针对病毒转录和复制的小分子。这些过程由一个包含 RNA 依赖性 RNA 聚合酶 (L) 和四聚体磷蛋白 (P) 的复杂体系催化。RSV P 将多种蛋白质募集到聚合酶复合物中，除了其寡聚化结构域外，它被认为是固有无序的。尽管它们在 RSV 转录和复制中起着关键作用，但 L 和 P 的结构仍然难以捉摸。在这里，我们描述了 RSV L 与四聚体 P 结合的 3.2-Å 冷冻电镜结构。该结构揭示了 P 的惊人触手状排列，每个四聚体采用独特的构象。该结构还合理地解释了抑制剂逃逸突变体和活减毒候选疫苗中观察到的突变。这些结果为确定 RSV 复制和转录的分子基础提供了框架，并应有助于设计有效的 RSV 抑制剂。
