Research led by USC Dornsife’s Ray Stevens of the Bridge Institute at the USC Michelson Center for Convergent Bioscience may lead to new or better treatments for patients with obesity. They’ve configured a key cell receptor that is the likely target for new therapies. (Illustration: Yekaterina Kadyshevskaya.)

Better obesity treatments may lie ahead after discovery of key protein structure

An international team of scientists, led by Raymond Stevens of the Bridge Institute at the USC Michelson Center for Convergent Bioscience, is investigating a protein in the brain that will likely be the target of improved obesity therapies. [1½ min read]

ByEmily Gersema May 4, 2020

A USC Dornsife-led international team of scientists has found the precise shape of a key player in human metabolism. The finding could lead the way to better treatments for obesity and other metabolic diseases.

For the study, the scientists focused on a protein in the brain known as the melanocortin 4 receptor (MC4R). This receptor helps with regulating the body’s energy balance by controlling how much energy is stored as fat. Mutations in the gene that encodes the MC4R protein are linked to severe childhood obesity and other forms.

Obesity has tripled worldwide since 1975, according to the World Health Organization.

“A lot of people think obesity is a lifestyle choice,” said Raymond Stevens, Provost Professor of Biological Sciences and Chemistry and co-director of the Bridge Institute at the USC Michelson Center for Convergent Bioscience. “That’s just not true in all cases. Some people have mutations of this gene. And if they have mutations of this gene, many cannot control their eating. It’s this receptor causing this issue in the brain.”

A path to advances in obesity treatments

Working with the iHuman Institute at ShanghaiTech University and the Life Sciences Institute at the University of Michigan, Stevens was interested in the MC4R as part of a larger effort to elucidate the structures of a class of proteins called G protein-coupled receptors that control many human functions. MC4R is among them.

University of Michigan scientists discovered MC4R and have been studying its biology and pharmacology for more than 25 years. The drug setmelanotide targets the MC4R to treat rare forms of syndromic obesity, which affects about 1 out of 1,500 people. However, the drug is not potent enough to treat dietary obesity — a more common form of the disease.

By determining the structure of MC4R, the scientists were able to see how it binds to and interacts with other drug molecules. Knowing how the protein is configured will enable scientists to develop and test new therapies that can more precisely treat obesity.

See USC News for more on the story >>

About the study

This research was supported by the National Institutes of Health (Cone Lab at Michigan), the Shanghai Municipal Government (Zhao Lab, ShanghaiTech) and the GPCR Consortium (Stevens Lab at USC).

Additional USC Dornsife authors were: Ariel H. Wein, Gye Won Han, Kyle McClary, Sanraj R. Mittal, Kylie Burdsall and Benjamin Stauch.

Disclosures: Raymond Stevens is the founder of a GPCR structure-based drug discovery company called ShouTi, and Roger Cone of the Life Sciences Institute at the University of Michigan is a founder of a melanocortin receptor drug discovery company called Courage Therapeutics.

Categories:

Topics: