New Method for Characterizing Protein Interactions

A novel approach to assessing the actions of medicines by matching them to their unique protein receptors has the potential to accelerate drug development, according to researchers from the University of Wisconsin-Milwaukee and the University of Glasgow. In a study that appeared today in Nature Methods, the team reported that their method reduces the time and labor of finding the protein receptors "with the right response" to drug candidates by several orders of magnitude.

"It opens up a huge playing field for finding drug targets and drug stratification," said Valerica Raicu, UW-Milwaukee professor of physics. "Using this method, we can characterize how each receptor responds differently to various drug candidates."

The researchers' method tracks oligomerization, which occurs when a receptor exists as a single subunit, but then shifts to a multi-structure—an oligomer—in the presence of the ligand (drug compound), or vice versa. "We used to think of these receptors as binary," said Raicu, lead author on the paper. "They were either activated by the compound or not. But now we are beginning to understand that, depending on the ligand, the same receptor can produce many different responses."

The researchers first tested the method using fused florescent proteins. Then they validated the method on a receptor for a growth factor where malfunction is often linked to cancer —the epidermal growth factor receptor. Activation of the receptor resulted in the generation of larger oligomers, as anticipated.  The team then applied their method to a member of the G protein-coupled receptor family. The effect of the association between ligands and receptors was shown in a matter of hours, compared to months using current technologies.

"This new method of characterizing protein interactions will be important in the stratification of different medicines that target the same receptor," said Graeme Milligan, Gardiner Chair of Biochemistry at the University of Glasgow. "It will allow us to understand why some drug candidates are effective while others are not and can potentially be applied to different classes of proteins that are targets in the treatment of many diseases."