Research Highlight: New understanding of gene-activating complexes may offer ‘a way forward’ for drug discovery efforts
New research from the University of Michigan Life Sciences Institute is challenging a long-held understanding of how two types of cellular proteins cooperate to activate genes.
The study, published in Proceedings of the National Academies of Sciences, improves the possibility of targeting these interactions with small-molecule drugs.
Every cell in our bodies includes the exact same set of genes. Differences between cell types — and, in many cases, between healthy cells or diseased cells — arise based on which genes are turned on in any given cell.
Proteins called transcriptional activators and coactivators play a crucial role in this process, by binding to each other and to DNA to activate a gene.
Previous research in the field indicated that these activators and coactivators recognize and latch onto each other through unspecific, almost random mechanisms. So although these complexes could present promising therapeutic targets for a variety of human diseases, their apparently loose organization has so far thwarted such efforts.
“This is important, because if this was a completely random mechanism, then there would be no way to build any sort of small molecule that could target the interaction with specificity,” says the study’s lead author, Matt Henley, Ph.D. “But if there’s something more complex going on, we can think about designing small-molecule strategies to interrupt these interactions.”
When researchers in the lab of LSI faculty member Anna Mapp, Ph.D., analyzed a representative set of activator-coactivator complexes, they discovered a much different molecular recognition model.
It gives us a way forward for drug discovery and also reinforces what we’ve been finding over the last few years: that these dynamic regions could be the best place to target with small molecules.
The team found that these dynamic complexes in fact bind with incredible specificity—even the slightest change in their sequence alters their binding arrangement. In addition, the coactivator appears to adjust its configuration in response to the activator, creating a more stable bond as the two proteins interact with one another.
“The findings show that these regions that most people would just completely disregard, because they don’t have any structure and they don’t seem to really contribute to affinity, actually form specific interactions,” says Mapp, who is also the associate dean for academic programs and initiatives at the U-M graduate school. “It gives us a way forward for drug discovery and also reinforces what we’ve been finding over the last few years: that these dynamic regions could be the best place to target with small molecules.”
Go to Article
“Unexpected specificity within dynamic transcriptional protein–protein complexes,” Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2013244117