4CB6: Structure Of Influenza A H5n1 Pb2 Cap-binding Domain With Bound Cap Analogue (compound 11)

Citation:
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 muM. 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.
PDB ID: 4CB6Download
MMDB ID: 114646
PDB Deposition Date: 2013/10/10
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 4CB6: monomeric; determined by author and by software (PISA)
Molecular Components in 4CB6
Label Count Molecule
Protein (1 molecule)
1
Polymerase Basic Subunit 2
Molecule annotation
Chemicals (7 molecules)
1
1
2
6
* Click molecule labels to explore molecular sequence information.

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