3RO5: Crystal Structure Of Influenza A Virus Nucleoprotein With Ligand

Citation:
Abstract
Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.
PDB ID: 3RO5Download
MMDB ID: 93571
PDB Deposition Date: 2011/4/25
Updated in MMDB: 2011/09
Experimental Method:
x-ray diffraction
Resolution: 2.66  Å
Source Organism:
Similar Structures:
Biological Unit for 3RO5: hexameric; determined by author and by software (PISA)
Molecular Components in 3RO5
Label Count Molecule
Proteins (6 molecules)
6
Nucleocapsid Protein
Molecule annotation
Chemicals (6 molecules)
1
6
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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