4CB7
Structure of Influenza A H5N1 PB2 cap-binding domain with bound cap analogue (compound 8e)
Summary for 4CB7
| Entry DOI | 10.2210/pdb4cb7/pdb |
| Related | 4CB4 4CB5 4CB6 |
| Descriptor | POLYMERASE BASIC SUBUNIT 2, GLYCEROL, 5-[2-(2-azanyl-7-methyl-6-oxidanylidene-1H-purin-9-ium-9-yl)ethanoyl]-2-oxidanyl-benzoic acid, ... (4 entities in total) |
| Functional Keywords | transcription, cap-binding inhibitors |
| Biological source | INFLUENZA A VIRUS |
| Total number of polymer chains | 2 |
| Total formula weight | 37209.08 |
| Authors | Pautus, S.,Sehr, P.,Lewis, J.,Fortune, A.,Wolkerstorfer, A.,Szolar, O.,Gulligay, D.,Lunardi, T.,Decout, J.L.,Cusack, S. (deposition date: 2013-10-10, release date: 2013-10-30, Last modification date: 2023-12-20) |
| Primary citation | 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 Cited by 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: 24134208DOI: 10.1021/JM401369Y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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