Chemists discover proton mechanism used by flu virus to infect cells

Oct 21, 2010
Mei Hong of Iowa State University and the Ames Laboratory, left, and Fanghao Hu of Iowa State used solid-state nuclear magnetic resonance spectroscopy to investigate the proton channel that connects a flu virus to a healthy cell. Credit: Photo by Bob Elbert/Iowa State University

The flu virus uses a shuttle mechanism to relay protons through a channel in a process necessary for the virus to infect a host cell, according to a research project led by Mei Hong of Iowa State University and the Ames Laboratory.

The findings are published in the Oct. 22 issue of the journal Science.

Hong, an Iowa State professor of chemistry and an associate of the U.S. Department of Energy's Ames Laboratory, said her research team used solid-state (NMR) spectroscopy to determine the structure and workings of the proton channel that connects the to a healthy cell.

She said a full understanding of that mechanism could help medical researchers design drugs that stop from moving through the channel.

That proton channel is an important part of the life cycle of a flu virus. The virus begins an infection by attaching itself to a healthy cell. The healthy cell surrounds the virus and takes it inside through a process called endocytosis. Once inside the cell, the virus uses a protein called M2 to open a channel. Protons from the healthy cell flow through the channel into the virus and raise its acidity. That triggers the release of the virus' into the healthy cell. The virus then hijacks the healthy cell's resources to replicate itself.

Hong and her research team – Fanghao Hu, an Iowa State doctoral student in chemistry; and Wenbin Luo, a former Iowa State doctoral student who is now a spectroscopist research associate at Penn State University – focused their attention on the structure and dynamics of the proton-selective amino acid residue, a histidine in the transmembrane part of the protein, to determine how the channel conducts protons. Their work was supported by grants from the National Science Foundation and the National Institutes of Health.

Two models had been proposed for the proton-conducting mechanism:

  • A "shutter" channel that expands at the charged histidine because of electrostatic repulsion, thus allowing a continuous hydrogen-bonded water chain that takes protons into the virus.
  • Or a "shuttle" model featuring histidine rings that rearrange their structure in some way to capture protons and relay them inside.
Hong's research team found that the histidine rings reorient by 45 degrees more than 50,000 times per second in the open state, but are immobile in the closed state. The energy barrier for the open-state ring motion agrees well with the energy barrier for proton conduction, which suggests that the M2 channel dynamically shuttles the protons into the virus. The chemists also found that the histidine residue forms multiple hydrogen bonds with water, which helps it to dissociate the extra proton.

"The histidine acts like a shuttle," Hong said. "It picks up a proton from the exterior and flips to let it get off to the interior."

The project not only provided atomic details of the proton-conducting apparatus of the flu virus, but also demonstrated the abilities of solid-state NMR.

"The structural information obtained here is largely invisible to conventional high-resolution techniques," the researchers wrote in their Science paper, "and demonstrates the ability of solid-state NMR to elucidate functionally important membrane protein dynamics and chemistry."

Explore further: Selenium compounds boost immune system to fight against cancer

Related Stories

A single VSOP can do a 'proton' magic!

Jun 16, 2008

International research group led by Yasushi Okamura, a professor in Japanese National Institute for Physiological Sciences, Okazaki, and Peter Larsson, a professor in Oregon Health & Science University, Oregon, US, found ...

Recommended for you

Molecules that came in handy for first life on Earth

Nov 24, 2014

For the first time, chemists have successfully produced amino acid-like molecules that all have the same 'handedness', from simple building blocks and in a single test tube. Could this be how life started. ...

Jumping hurdles in the RNA world

Nov 21, 2014

Astrobiologists have shown that the formation of RNA from prebiotic reactions may not be as problematic as scientists once thought.

New computer model sets new precedent in drug discovery

Nov 18, 2014

A major challenge faced by the pharmaceutical industry has been how to rationally design and select protein molecules to create effective biologic drug therapies while reducing unintended side effects - a challenge that has ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.