In a Yale University-led study, researchers have revealed the 3D structure of beta-Klotho, a protein known to have a hand in longevity. The work was published yesterday in Nature and highlights the protein's mechanism and therapeutic potential.
The research team used X-ray crystallography to look at the 3D structure and discovered several findings.
First, they found that beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced due to starvation. When bound to beta-Klotho, FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss. These new understandings can help guide treatments for conditions such as type 2 diabetes.
"Like insulin, FGF21 stimulates metabolism including glucose uptake," said senior author Joseph Schlessinger. 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 team also found evidence on how glycosidase, a structurally-related enzyme that breaks down sugars, has evolved into a receptor for a hormone that lowers blood sugar.
The group believes that finding the structure of beta-Klotho can lead to many different treatments for multiple diseases. They see that if drugs are developed that enhance the pathway, then researchers can target obesity and diabetes. On the other hand, if drugs are created to block the pathway, therapies for conditions like liver cancer and bone diseases could be generated.
"The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward," Schlessinger said.