Influenza ‘Cap Snatcher’ Identified


Seasonal epidemics of the influenza virus continue to kill hundreds of thousands of people annually, and the increasing incidence of resistance to approved drugs means that there is a pressing need for new therapies. The viral polymerase is an attractive target for drug development and a newly reported high-resolution crystal structure of the polymerase PA domain should provide useful insights for inhibitor design.

Influenza PA domain crystal structureIn eukaryotic cells, mRNA must be capped at the 5’-end for efficient translation. Cap structures, consisting of N7-methylated guanine units, also assist in transport of mRNA from nucleus to cytoplasm and protect mRNA from degradation by 5′ exonucleases. The viral polymerase ‘steals’ caps from cellular mRNA in a process known as ‘cap-snatching’ and attaches them to viral mRNAs so that these can be translated into new viral proteins.

The polymerase is a heterotrimer comprising three subunits, PA, PB1 and PB2, and whilst previous studies had shown that PB2 plays a role in cap-binding, PB1 was believed to be responsible for ‘cap-snatching’. The new study, published online on February 4th in the journal Nature, clearly shows, however, that the PA subunit contains the endonuclease active site and plays a crucial role in cleaving the cap from host mRNA. The active site, which is conserved in all influenza viruses, contains a histidine residue together with a cluster of three acidic residues that bind two manganese ions in a configuration similar to that observed in other two-metal-dependent endonucleases. Inhibition of cap-cleavage by the endonuclease would be an effective anti-viral strategy since it would effectively block synthesis of viral proteins.

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