9pmr
Influenza PA-N Endonuclease I38T mutant with compound 2 ((6M)-6-(2-ethylphenyl)-3,4-dihydroxypyridine-2-carboxylic acid)
Structural highlights
FunctionPA_I09A0 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 PubMedThe influenza virus causes a significant burden of illness each year. Although vaccination is the most effective method to prevent seasonal influenza infection, viral escape mechanisms make vaccine composition difficult to predict. Antivirals are crucial for decreasing rates of morbidity and mortality from influenza viral infection. The newest anti-influenza drugs target the RNA-dependent RNA polymerase acidic N-terminal (PA(N)) endonuclease, a critical component of influenza viral replication machinery. This study examines the structure of inhibitors of PA(N) that utilize a hydroxypyridinone-based metal-binding pharmacophore (MBP). Specifically, this report explores how the size of substituent groups impacts the binding conformation and affinity of a series of compounds against both wild-type (WT) and resistance mutant strains, I38T and E23K. Co-crystal structures revealed that the distance between compounds and enzyme residue 38 was conserved to maintain strong interactions, resulting in deviations from ideal coordination geometries at the active site metal centers. This suggests the interactions with residue 38 with each compound is important and can impact inhibitor potency as a consequence of distortions in the metal binding geometry of the compounds. Substituent size versus metal binding of inhibitors with variants of influenza endonuclease.,Kohlbrand AJ, Stokes RW, Sankaran B, Cohen SM J Inorg Biochem. 2026 Apr;277:113210. doi: 10.1016/j.jinorgbio.2025.113210. Epub , 2025 Dec 31. PMID:41512630[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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