How does a single nucleotide change make influenza virus resistant to a drug?

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Sandra Porter
Two protein structures from an avian influenza virus are shown below. One form of the protein makes influenza virus resistant to Oseltamivir (Tamiflu®) Don't worry, these proteins aren't from H5N1, but they do come from a related influenza virus that also infects birds.

One protein structure is from a strain that is sensitive to an anti-viral drug called "Tamiflu®". The other structure is from the same virus, except there's a slight difference. A single base change in the viral RNA changed the codon that tells the translation machinery which amino acid to put into the protein, so now a different amino acid is substituted for the original. This substitution mutation makes the virus resistant to the drug. i-0f3bd3c6757be8da8efbd08d876984c5-r_sm.gif Tamiflu®, the drug, is the large lumpy thing in the middle of the image, on the left. The colors of the lumps represent different elements: nitrogens, carbons, and oxygens. The red tubes represent the rest of the structure. On the right is a lumpy amino acid that forms hydrogen bonds with the drug. (Oh that drug is sooo mean! It just kills me to think about it!) That was NOT what I meant by sensitive strain. Move your mouse over the superimposed structures and you'll see how the structure changes when there are different amino acids in that position. Remember, the only different between the sensitive strain and the resistant strain is that one amino acid. Why do you think this virus is resistant to the drug? A Beginner's Guide to Molecular Structures The neat thing is that working with structures like this and looking at the differences is something that anyone can do. All you need is a computer (Windows, Mac OS X, and UNIX work best as far as I can tell), Cn3D (a freely available program from the NCBI), and a connection to the internet to get the superimposed structures. Once you've got the structures, you can work with them on your computer. I've been helping high school and college students and teachers learn how to get structures like this and superimpose them for the past few years in classes and teacher workshops (i.e. Tastes like chicken). Now, finally, I put these activities and answers to workshop questions into a book, A Beginner's Guide to Molecular Structures. It covers:
  • how to use Entrez and find structures
  • how to use a variety of structure databases at the NCBI, like PubChem, the Conserved Domain Database, CDART, MMDB, and VAST
  • how to interpret genetic nomenclature
  • how to use Cn3D to work with and annotate structures
  • how to obtain superimposed structures and see the differences.
The activities cover topics like working with green fluorescent protein, examining what happens to proteins when genes contain polymorphisms (what is a SNP), and of course, the activity above with influenza. And all the activities have been tested by students. Solving structures is hard, but according to my student interns, Cn3D is easier than most video games. Read a review by the famous Dr. Hsien-Hsien Lei. After all, why should scientists have all the fun?

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