In a recent Yale-led study, researchers revealed the three-dimensional structure of one of these proteins, beta-Klotho, illuminating its intricate mechanism and therapeutic potential.
The study findings, published in Nature, could have implications for therapies developed to treat a wide range of medical conditions, including diabetes, obesity, and certain cancers, the researchers said.
To understand how beta-Klotho works, the research team used X-ray crystallography, a technique that provides high-resolution, three-dimensional views of these proteins. First, beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation. This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients, the researchers said. “Like insulin, FGF21 stimulates metabolism including glucose uptake,” said Joseph Schlessinger, senior author and chair of pharmacology at Yale School of Medicine.
“In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21.” The authors also describe a new variant of FGF21 that has 10 times higher potency and cellular activity.