6EUY

Structure of the midlink and cap-binding domains of influenza A polymerase PB2 subunit with a bound azaindazole cap-binding inhibitor

6EUY の概要

• エントリーDOI: 10.2210/pdb6euy/pdb
• 分子名称: Polymerase basic protein 2, (2~{S},3~{S})-3-[[5-fluoranyl-2-(5-fluoranyl-1~{H}-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid, SULFATE ION (3 entities in total)
• 機能のキーワード: influenza a polymerase pb2 subunit cap-binding domain cap-binding inhibitor, rna binding protein
• 由来する生物種: Influenza A virus (A/Victoria/3/1975(H3N2))
• 細胞内の位置: Virion : P31345
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 99350.49

構造登録者

Cusack, S.,Gaudon, S. (登録日: 2017-10-31, 公開日: 2017-12-13, 最終更新日: 2024-01-17)

主引用文献

Pflug, A.,Gaudon, S.,Resa-Infante, P.,Lethier, M.,Reich, S.,Schulze, W.M.,Cusack, S.
Capped RNA primer binding to influenza polymerase and implications for the mechanism of cap-binding inhibitors.
Nucleic Acids Res., 46:956-971, 2018

PubMed Abstract: Influenza polymerase uses short capped primers snatched from nascent Pol II transcripts to initiate transcription of viral mRNAs. Here we describe crystal structures of influenza A and B polymerase bound to a capped primer in a configuration consistent with transcription initiation ('priming state') and show by functional assays that conserved residues from both the PB2 midlink and cap-binding domains are important for positioning the capped RNA. In particular, mutation of PB2 Arg264, which interacts with the triphosphate linkage in the cap, significantly and specifically decreases cap-dependent transcription. We also compare the configuration of the midlink and cap-binding domains in the priming state with their very different relative arrangement (called the 'apo' state) in structures where the potent cap-binding inhibitor VX-787, or a close analogue, is bound. In the 'apo' state the inhibitor makes additional interactions to the midlink domain that increases its affinity beyond that to the cap-binding domain alone. The comparison suggests that the mechanism of resistance of certain mutations that allow virus to escape from VX-787, notably PB2 N510T, can only be rationalized if VX-787 has a dual mode of action, direct inhibition of capped RNA binding as well as stabilization of the transcriptionally inactive 'apo' state.

PubMed: 29202182
DOI: 10.1093/nar/gkx1210

実験手法

X-RAY DIFFRACTION (3 Å)