2w69

INFLUENZA POLYMERASE FRAGMENT

spinqualitylabelsall models 2w69, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2w69 is a 3 chain structure with sequence from Influenza a virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MN, SO4 Resources: FirstGlance, OCA, RCSB, PDBsum Function [PA_I75A3] Implicated in endonuclease cleavage of capped RNA primers. Displays an elongation factor activity in viral RNA synthesis. Dispensable for viral transcription, but not replication. Publication Abstract from PubMed The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.,Dias A, Bouvier D, Crepin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW Nature. 2009 Feb 4. PMID:19194459 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also RNA polymerase

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