New Understanding on How the Flu Virus Replicates
Scientists have cracked another piece of the puzzle of how the flu virus is multiplied in the cells of our body. To replicate, a virus particle must pass its genetic material to the host cell. For the flu virus this is triggered by the passage of hydrogen ions into the viral core using a special protein in the membrane sheath surrounding the viral particle. This protein, called M2, serves as a channel for the hydrogen ions.
An interdisciplinary team of scientists at Florida State University and Brigham Young University have now determined the atomic structure of the M2 channel in an environment that closely mimics the membrane sheath of the virus particle. Determining the structure in this "native-like" environment is important because its structure is very sensitive to its environment. This new structure has allowed these scientists to model how the M2 protein channels hydrogen ions into the viral interior.
To determine the M2 structure, Tim Cross and his students in the Department of Chemistry and Biochemistry at FSU used a technique called solid-state nuclear magnetic resonance with unique instrumentation at the National High Magnetic Field Laboratory to obtain data on the structure in a "native-like" environment. Huan-Xiang Zhou and his students in the Department of Physics at FSU then used the data to compute the atomic structure in the same 'native-like environment. The native function of the protein was confirmed in assays performed by David Busath and his student in the Department of Physiology and Developmental Biology at BYU. The research is to be published in an upcoming issue of Science. The first author of the paper is Mukesh Sharma.
In the structure, four copies of the M2 polypeptide chain come together to form a pore that spans the membrane sheath, generating the passageway for hydrogen ions to enter the viral particle. This passage is delicately controlled by two amino acids, a histidine and a tryptophan, from each of the M2 chains. Their tetrameric cluster, referred to as the histidine-tryptophan quartet, generates novel chemistry and shepherds hydrogen ions through the channel, while preventing other small ions from from entering the virus.
Two drugs, Symmetrel and Flumadine, target the M2 protein but the CDC is now recommending against their use because recent viral strains have developed drug resistance. The M2 structure described here provides a new opportunity for developing drugs that can overcome this drug resistance.
The National High Magnetic Field Laboratory develops and operates state-of-the-art, high-magnetic-field facilities that faculty and visiting scientists and engineers use for research. The laboratory is sponsored by the National Science Foundation and the state of Florida. To learn more visit www.magnet.fsu.edu.
