4CB5

Structure of Influenza A H5N1 PB2 cap-binding domain with bound cap analogue (compound 8f)

4CB5 の概要

• エントリーDOI: 10.2210/pdb4cb5/pdb
• 関連するPDBエントリー: 4CB4
• 分子名称: POLYMERASE BASIC SUBUNIT 2, 9-N-(3-CARBOXY-4-HYDROXYPHENYL)KETOMETHYL-7-N-METHYLGUANINE, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: transferase, cap-binding inhibitors
• 由来する生物種: Influenza A virus (A/duck/Shantou/4610/2003(H5N1))
• 細胞内の位置: Host nucleus : Q2LG68
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19337.63

構造登録者

Pautus, S.,Sehr, P.,Lewis, J.,Fortune, A.,Wolkerstorfer, A.,Szolar, O.,Gulligay, D.,Lunardi, T.,Decout, J.L.,Cusack, S. (登録日: 2013-10-10, 公開日: 2013-10-30, 最終更新日: 2023-12-20)

主引用文献

Pautus, S.,Sehr, P.,Lewis, J.,Fortune, A.,Wolkerstorfer, A.,Szolar, O.,Gulligay, D.,Lunardi, T.,Decout, J.L.,Cusack, S.
New 7-Methyl-Guanosine Derivatives Targeting the Influenza Polymerase Pb2 CAP-Binding Domain
J.Med.Chem., 56:8915-, 2013

PubMed Abstract: The heterotrimeric influenza virus polymerase performs replication and transcription of viral RNA in the nucleus of infected cells. Transcription by "cap-snatching" requires that host-cell pre-mRNAs are bound via their 5' cap to the PB2 subunit. Thus, the PB2 cap-binding site is potentially a good target for new antiviral drugs that will directly inhibit viral replication. Docking studies using the structure of the PB2 cap-binding domain suggested that 7-alkylguanine derivatives substituted at position N-9 and N-2 could be good candidates. Four series of 7,9-di- and 2,7,9-trialkyl guanine derivatives were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analogue. Three synthesized compounds display potent in vitro activity with IC50 values lower than 10 μM. High-resolution X-ray structures of three inhibitors in complex with the H5N1 PB2 cap-binding domain confirmed the binding mode and provide detailed information for further compound optimization.

PubMed: 24134208
DOI: 10.1021/JM401369Y

実験手法

X-RAY DIFFRACTION (1.5 Å)