Constantinides Amanda, Gumpper Ryan, Severin Chelsea, Luo Ming
Department of Chemistry, Georgia State University, 50 Decatur Street, Atlanta, GA 30303, USA.
Acta Crystallogr F Struct Biol Commun. 2018 Mar 1;74(Pt 3):122-127. doi: 10.1107/S2053230X18000894. Epub 2018 Feb 26.
In the face of increasing drug resistance and the rapidly increasing necessity for practicality in clinical settings, drugs targeting different viral proteins are needed in order to control influenza A and B. A small molecule that tenaciously adheres to the PB2cap binding domain, part of the heterotrimeric RNA polymerase machinery of influenza A virus and influenza B virus, is a promising drug candidate. Understanding the anatomic behavior of PB2cap upon ligand binding will aid in the development of a more robust inhibitor. In this report, the anatomic behavior of the influenza A virus PB2cap domain is established by solving the crystal structure of native influenza A virus PB2cap at 1.52 Å resolution. By comparing it with the ligand-bound structure, the dissociation and rotation of the ligand-binding domain in PB2cap from the C-terminal domain is identified. This domain movement is present in many PB2cap structures, suggesting its functional relevance for polymerase activity.
面对日益增加的耐药性以及临床环境中对实用性的快速增长的需求，为了控制甲型和乙型流感，需要针对不同病毒蛋白的药物。一种小分子紧密附着于PB2帽结合结构域，该结构域是甲型流感病毒和乙型流感病毒异源三聚体RNA聚合酶机制的一部分，是一种有前景的候选药物。了解PB2帽在配体结合时的构象变化将有助于开发更有效的抑制剂。在本报告中，通过以1.52 Å分辨率解析甲型流感病毒天然PB2帽的晶体结构，确定了其构象行为。通过将其与配体结合结构进行比较，确定了PB2帽中配体结合结构域相对于C末端结构域的解离和旋转。这种结构域运动存在于许多PB2帽结构中，表明其与聚合酶活性的功能相关性。
