The discovery of the protein configuration could lead to more effective treatments for obesity.

The researchers have revealed the precise shape of a key player in human metabolism, which could open the door to better treatments for obesity and other metabolic disorders.

The research, scheduled to be published on April 24 in the journal. Science, focused on a protein in the brain called the melanocortin 4 receptor, or MC4R. This receptor plays a crucial role in regulating the body’s energy balance by controlling the amount of energy stored as fat.

Mutations in the gene encoding the MC4R protein are the most common genetic cause of early-onset obesity, affecting approximately 1 in 1,500 people.

Raymond Stevens, director of the Bridge Institute at the Michelson Center for Converged Bioscience at the University of Southern California and founding director of the iHuman Institute at ShanghaiTech University, 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, of which MC4R is a member.

When Stevens and his team started to tackle the MC4R structure, they turned to Roger Cone and his colleagues at the University of Michigan Institute for Life Sciences.

Scientists at the Cone lab discovered MC4R and have been studying its biology and pharmacology for over 25 years. In that time, at least four drugs have been developed to attack melanocortin receptors in humans. One of these drugs, setmelanotide, acts on MC4R to treat rare forms of syndromic obesity. But it’s not powerful enough to treat more common forms of obesity, such as food obesity, said Cone, who was a lead author on the study.

Working at all three institutions, researchers Yu Jing and Luis Giménez led the team to determine the structure of MC4R, and discovered some unexpected characteristics of the protein that shed new light on how it binds and interacts with other molecules.

For example, they found a binding of calcium ions to both MC4R and the primary molecule to which the receptor binds. This instance of the bound calcium ion was the first time that Stevens and his group determined the structures of many members of this large class of proteins.

“At first it seemed more like a scientific curiosity. But then other experiments revealed that calcium is really necessary for receptor function,” said Stevens, who was also the study’s lead author. “Imagine a lock and key situation; in this case, we discovered that there is a large key and a small key, and that we need them to unlock the receiver.”

Lex Van Der Ploeg, former chief scientific officer for Rhythm Pharmaceuticals, the company that developed setmelanotide, believes the findings open a new path to structure-based design of agonists and antagonists for the melanocortin receptor family.

“These discoveries may allow the development of melanocortin receptor-targeted pharmaceuticals for various therapeutic applications,” said Van Der Ploeg, who was not involved in this study.

Cone and Stevens highlight the findings as an example of the importance and power of international collaboration.

“We were able to contribute our knowledge of MC4R to help promote structural biology studies,” said Cone, who serves as director of the LSI and professor of molecular and integrative physiology at the U-M School of Medicine. “And the key structural findings from researchers at USC and ShanghaiTech are helping us answer more questions about how this receptor works in human metabolism.”