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流感 A 聚合酶 PB2 亚基治疗抑制的结构基础。

Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit.

机构信息

Structural and Biophysical Chemistry, Novartis Institutes for BioMedical Research, Emeryville, CA, USA.

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, CA, USA.

出版信息

Sci Rep. 2017 Aug 24;7(1):9385. doi: 10.1038/s41598-017-09538-x.

Abstract

Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.

摘要

流感病毒使用一种独特的机制启动病毒转录,名为“帽抢夺”。病毒的异三聚体 RNA 聚合酶的 PB2 亚基结合细胞前体 mRNA 的帽结构,促进其被 PA 亚基切割。得到的 11-13 个加帽寡聚物被 PB1 聚合酶亚基用于启动病毒蛋白的转录。VX-787 是流感 A 病毒前体 mRNA 帽结合蛋白 PB2 的抑制剂。该临床阶段化合物被证明结合 PB2 的最小帽结合结构域以抑制帽抢夺机制。然而,在 PB2 亚基的扩展形式的背景下,该分子的结合仍然难以捉摸。在这里,我们生成了一系列 PB2 截断物,以鉴定 PB2 蛋白在病毒异三聚体蛋白中的结构代表。我们展示了 VX-787 与 PB2 构建体结合的晶体结构,该构建体再现了 VX-787 在体外的抗病毒活性。该共结构揭示了比以前鉴定的更广泛的相互作用,并提供了对观察到的耐药谱、亲和力、结合动力学和 VX-787 诱导的构象重排的深入了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/279c/5571044/174e095263f4/41598_2017_9538_Fig1_HTML.jpg

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