Drugs that work by blocking the function of a protein from the outside also disrupt the protein's internal workings, according to new research from the University of North Carolina at Chapel Hill.
The discovery, made by scientists at the UNC Eshelman School of Pharmacy and published in the March 11 issue of the journal Structure , opens the door to the possibility of targeting proteins with drugs in new ways. The study is the first to take a comprehensive look at the changes that take place within the molecular machinery of a protein when it binds with a drug.
"Previous studies have looked at the movement within proteins, and they've looked at how the structure of proteins change when drugs bind to them," said Andrew Lee, Ph.D., an associate professor in the pharmacy school and senior author of the study. "However no one has looked to see how actual movement is affected when drugs bind until now."
Using sophisticated spectroscopic technology, Lee and his colleagues studied how two drugs, the cancer drug methotrexate and the antibiotic trimethoprim, affected the internal mechanics of a particular protein - an enzyme called DHFR - in a strain of E. coli bacteria.
Only in the past decade have scientists become convinced of the importance of movement in the function of protein enzymes, Lee said. Those movements give proteins the energy needed to complete the biological processes for which they are responsible. The motions are very quick; some of them are so fast they are measured in picoseconds, or trillionths of a second, and appear as vibrations rather than large movements. "The proteins almost appear to be breathing," Lee said.
"We found that when we bound a drug to the protein in our study, parts of the protein away from the receptor site stop moving," Lee said. "The drug decoupled the global motion that was occurring throughout the enzyme."