Influenza Virus Sialidase Structure and Mechanism

The first three-dimensional structure of influenza A virus sialidase was solved in 1983 to 2.9 A resolution, using X-ray data for two crystalline N2 sialidases as pronase-released heads [61,62]. This work gave detail to the known tetrameric form of the protein. Crystals soaked with free NeuSAc, the product of catalysis, indicated that the active site was a deep pocket on the top surface of each subunit [62]. 

The six-bladed P-propeller-like domain is now recognized as the canonical siali-dase structure, found in each of the viral, bacterial, trypanosomal, and human exo-sialidases crystallized [63-66], despite wide differences in sequence similarities [67]. Key catalytic residues in the active site are also well conserved (reviewed in [63]). 

Antigenic determinants were found across the top surface of the sialidase monomer and encircling the active site [62], Of importance for inhibitor development, the active site was seen to contain a large number of amino acids that were conserved in all influenza A and B virus sialidase sequences known to that time [34,62]. This suggested that the active site residues were under pressure to remain constant [69], and that this was an invariant area of the sialidase that could be targeted for inhibitor development against the otherwise highly mutable [4] protein. 

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