6syi
From Proteopedia
C-TERMINAL DOMAIN OF INFLUENZA POLYMERASE PA SUBUNIT AND OPTIMIZED SMALL PEPTIDE INHIBITOR
Structural highlights
FunctionD4HIS2_9INFA Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity.[HAMAP-Rule:MF_04063] Publication Abstract from PubMedInfluenza viruses can cause severe respiratory infections in humans, leading to nearly half a million deaths worldwide each year. Improved antiviral drugs are needed to address the threat of development of novel pandemic strains. Current therapeutic interventions target three key proteins in the viral life cycle: neuraminidase, the M2 channel and RNA-dependent-RNA polymerase. Protein-protein interactions between influenza polymerase subunits are potential new targets for drug development. Using a newly developed assay based on AlphaScreen technology, we screened a peptide panel for protein-protein interaction inhibitors to identify a minimal PB1 subunit-derived peptide that retains high inhibition potential and can be further modified. Here, we present an X-ray structure of the resulting decapeptide bound to the C-terminal domain of PA polymerase subunit from pandemic isolate A/California/07/2009 H1N1 at 1.6 A resolution and discuss its implications for the design of specific, potent influenza polymerase inhibitors. structural characterization of the interaction between the C-terminal domain of the influenza polymerase PA subunit and an optimized small peptide inhibitor.,Hejdanek J, Radilova K, Pachl P, Hodek J, Machara A, Weber J, Rezacova P, Konvalinka J, Kozisek M Antiviral Res. 2020 Nov 6;185:104971. doi: 10.1016/j.antiviral.2020.104971. PMID:33166574[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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