How a Structural Discovery Could Aid in Future Drug Design

Researchers determine how to better predict a drug’s course of action.

Ever wonder how two different signals within the body get turned into one output?

So have scientists at the Scripps Research Institute. In a recent study, researchers uncovered the structural details of how some proteins interact to turn two different signals into a single integrated output. The findings could help with future drug design, as scientists learn to fine tune the signal between partnered proteins and the drug’s course of action.

“Thyroid, vitamin D and retinoid receptors all rely on integrated signals — their own signal plus a partner receptor,” said TSRI Associate Professor Kendall Nettles, who led the study with TSRI colleague Associate Professor Douglas Kojetin. “These new findings will have important implications for drug design by clearly defining exactly how these signals become integrated, so we will be able to predict how changes in a drug’s design could affect signaling.”

The scientists were able to determine the mechanism through which two signaling pathways turn into one integrated signal by utilizing technologies such as nuclear magnetic resonance, X-ray crystallography, and hydrogen/deuterium exchange mass spectrometry.

The study focused on a small subset of nuclear receptors, a large family of proteins that regulate gene expression in response to signals from various binding partners, including steroids and fats. When the receptors recognize the presence of the binding partners, they send out new signals that allow other cellular processes to begin.

“Nuclear receptors bind different types of molecules, and some of these receptors physically interact with each other to integrate different signals,” Kojetin said. “Earlier studies basically accepted this without any structural evidence for communication between receptors. This is the first time that anyone has looked at what’s actually going on at the atomic level.”

Now that scientists have reached this new understanding about the processes of turning two different signals into a single, integrated signal, the future of drug design is much brighter as scientists will be able to better target the drug’s course of action. As further developments take place and researchers uncover more information, the science of the human body becomes clearer little by little.