Imagine a key that opens a pin tumbler lock. A very similar key can also fit into the lock, but upside down in comparison to the first key.
Biochemist Eric Ortlund and colleagues have obtained analogous results in their study of how potential diabetes drugs interact with their target, the protein LRH-1. Their research, published in Journal of Biological Chemistry, shows that making small changes to LRH-1-targeted compounds makes a huge difference in how they fit into the protein’s binding pocket.
This research was selected as “Paper of the Week” by JBC and is featured on the cover of the December 2 issue.
LRH-1 (liver receptor homolog-1) is a nuclear receptor, a type of protein that turns on genes in response to small molecules like hormones or vitamins. LRH-1 acts in the liver to regulate metabolism of fat and sugar.
Previous research has shown that activating LRH-1 decreases liver fat and improves insulin sensitivity in mice. Because of this, many research teams have been trying to design synthetic compounds that activate this protein, which could have potential to treat diabetes and nonalcoholic fatty liver disease. This has been a difficult task, because not much is known about how synthetic compounds interact with LRH-1 and switch it into the active state. Read more