Influenza C virus and bovine coronavirus esterase reveal a similar catalytic mechanism: new insights for drug discovery.
Both, the influenza C (INF-C) virus haemagglutinin esterase fusion and bovine coronavirus (BCoV) haemagglutinin esterase surface glycoproteins exhibit a lectin binding capability and a receptor-destroying 9-O-acetyl esterase activity that recognise 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac(2))-containing glycans. Here we report nuclear magnetic resonance and molecular modelling studies on the 9-O-acetyl esterase showing that the alpha-configured Neu5,9Ac(2) is strictly preferred by the INF-C and BCoV esterases. Interestingly, we have discovered that the INF-C esterase function releases acetate independently of the chemical nature of the aglycon moiety, whereas subtle differences in substrate recognition were found for BCoV esterase. Analysis of the apo and complexed X-ray crystal structure of INF-C esterase revealed that binding of 9-O-acetylated N-acetylneuraminic acids is a dynamic process that involves conformational rearrangement of serine-57 in the esterase active site. This study provides valuable insights towards the design of drugs to combat INF-C virus and coronavirus infections causing outbreaks of upper respiratory infections and severe diarrhea in calves, respectively.
Mayr
Juliane
J
Applied Biotechnology, Department of Cell Biology, University of Salzburg, Salzburg, Austria.
Haselhorst
Thomas
T
Langereis
Martijn A
MA
Dyason
Jeffrey C
JC
Huber
Wolfgang
W
Frey
Barbara
B
Vlasak
Reinhard
R
de Groot
Raoul J
RJ
von Itzstein
Mark
M
D000107:Acetylation; D000818:Animals; D055162:Biocatalysis; D002236:Carbohydrate Conformation; D020134:Catalytic Domain; D002417:Cattle; D017938:Coronavirus, Bovine / Q000201:enzymology*; D015195:Drug Design; D055808:Drug Discovery; D006389:Hemagglutinins, Viral / Q000378:metabolism*; D009982:Gammainfluenzavirus / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D014760:Viral Fusion Proteins / Q000378:metabolism*
D006389:Hemagglutinins, Viral; D014760:Viral Fusion Proteins; C060814:hemagglutinin esterase; D019158:N-Acetylneuraminic Acid