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H274Y (Histidine to Tyrosine) is the most common mutation conferring resistance to the drug Tamiflu in the neuraminidase N1 of Influenza A (e.g. H1N1, H5N1). Although resistant, this mutant N1 still binds Tamiflu weakly, and a crystal structure was obtained, 3ckz. Below, this is compared to the wild type, 2hu4], using structural alignment of a single protein chain:Tamiflu complex from each.

Why is the affinity of Tamiflu reduced by the mutation H274Y? Use the scenes below to help answer this question.

Tamiflu is shown as thick sticks. Atoms contacting Tamiflu (4 Å) are shown as balls. Amino acids that contain contacting atoms, plus amino acid 274, are shown as thin sticks. All other amino acids are hidden.

Influenza neuraminidase N1:

Atoms are colored by element: C, N, O (in protein), O (in water).

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Eric Martz

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