Additional Mechanism Regulates Protein Activity

A University of Arkansas researcher and his colleagues have discovered a new mechanism that regulates the interaction of proteins in cell membranes. This discovery may lead to more efficient drug screening and possibly different methods for fighting infections.

Roger Koeppe, University Professor of chemistry and biochemistry, Thomas Suchnya, Frederick Sachs and Phillip Gottlieb of SUNY Buffalo and Sonya Tape and Olaf Andersen of Weil Medical College of Cornell University report their findings in the July 8, 2004, issue of Nature.

Scientists have explained the interaction of antibiotics using a “lock and key,” model, where a small drug of a certain shape (the key) binds to a bacterial protein (the lock) to neutralize it and prevent the spread of an infection.

In the Nature paper, the researchers show that this model is not the only rule in drug-protein interaction. They discovered that the mirror image of a peptide isolated from tarantula venom had the same effect on a certain type of pressure-sensitive cell membrane protein channel as did the natural peptide toxin – a finding that violates the “lock and key” model because the toxin and its mirror image have different shapes.

Further, they found that the mirror images of bacterial gramicidin channels, developed in the Koeppe laboratory at the University of Arkansas, respond much like natural gramicidin channels to both the tarantula toxin and its mirror image

“The effect is similar in different chemical systems,” Koeppe said. The researchers have concluded that, instead of working by the traditional “lock and key” model, the peptide toxin and its mirror image change the shape or curvature of the lipid bilayer, or the protective “skin” of the cell membrane.

This finding opens up a host of new applications, including the possibility of using mirror image proteins for drug therapies. Often, the mirror image peptides or proteins are biologically more stable and, if developed into drugs, could last longer in the body, Koeppe said. Also, the mirror image proteins don’t activate the body’s immune system as effectively, which could have a positive impact on organ transplant acceptance.

The gramicidin channel system also could be used to screen the generalized effects of potential drugs on the mechanical properties of lipid bilayer membranes.

“When a company develops a drug, they usually only want it to affect one thing,” Koeppe said. If a drug alters cell membrane properties globally, then its effects may prove too general, he said.

“If new drugs could be tested on gramicidin channels, it could speed up predictions of what such drugs would do in other systems,” Koeppe said. The cell membrane effects may be desirable or undesirable depending upon the system. “This could help companies find out early if there is a problem instead of investing three years and then finding out.”