Scientists from Scripps Florida have revealed a new picture of how biochemical information can be transmitted through the modification of a protein.
Previously, scientists believed that during the pairing of proteins and their binding partners (“ligands”), proteins modified their shape while ligands remained stable. The new study shows this one-size-fits-all solution is not entirely accurate.
Instead, the ligand actually samples a variety of binding modes while the protein also modifies its shape, a process that results in their pairing and changes in the protein critical for its function.
These new findings, published in the journal Structure, could affect future drug design.
“Using a multidisciplinary approach, we gleaned something from our data that no one else has,” said Douglas Kojetin, an assistant professor on the Scripps Florida campus who led the study. “The conventional wisdom is that ligands bind in one orientation but our study shows that they can bind in multiple modes. That means if we can optimize a ligand to bind in mode B rather than mode A, we might be able to select the therapeutic results we want.”
The new study—which used a number of complementary technologies including NMR spectroscopy and hydrogen/deuterium exchange (HDX) coupled to mass spectrometery, combined with previous x-ray crystallography analyses—provides detailed insights into the real-time actions of molecules that could never be determined with a single technology.
Specifically, the researchers revealed insights into ligand and receptor dynamics in the nuclear receptor known as PPARγ (peroxisome-proliferator-activated receptor). PPARγ has been implicated in metabolic diseases including obesity, diabetes, and atherosclerosis.
The study also found that various gradations in these ligands influence the dynamics of this exchange, adding another layer of complexity. “One of the compounds, MRL24, binds to the receptor and has anti-diabetic efficacy, but doesn’t activate it very well,” Kojetin said. “This is what you want because when the receptor is activated you get side effects such as weight gain and brittle bones.”
