Researchers at the University of Michigan in Ann Arbor have helped unveil the precise shape of a key protein in human metabolism. The finding could open the door to better treatments for obesity and other metabolic disorders.
The research was published today in the journal Science. It centered on a protein in the brain called the melanocortin 4 receptor, or MC4R. The receptor helps regulate the body’s energy balance by controlling how much energy is stored as fat.
Mutations in the gene that encodes the MC4R protein are the most common genetic cause of early-onset obesity, affecting about one in every 1,500 people.
Roger Cone, director at the University of Michigan Life Sciences Institute, and scientists in his lab discovered MC4R and have been studying its biology and pharmacology for more than 25 years. Since then, at least four drugs have been developed to target melanocortin receptors in humans. One of these drugs, setmelanotide, acts at the MC4R to treat rare forms of syndromic obesity. It is not potent enough to treat more common forms of obesity, such as dietary obesity, says Cone, who was a senior author of the study.
The study spanned three universities – Raymond Stevens, director of the Bridge Institute in the University of Southern California Michelson Center for Convergent Bioscience and founding director of the iHuman Institute at ShanghaiTech University, was interested in the protein as part of a larger effort to elucidate the structures of a class of proteins called G protein-coupled receptors. MC4R is in this class.
Stevens and his team turned to Cone and his colleagues as he began to study MC4R’s structure.
“We were able to contribute our knowledge of the MC4R to help further the structural biology studies,” says Cone, who is also a professor of molecular and integrative physiology at the U-M Medical School. “And key structural findings from the USC and ShanghaiTech researchers are helping us answer more questions about how this receptor functions in human metabolism.”
Researchers discovered some unexpected characteristics of the protein that shed new light on how it binds to and interacts with other molecules.
For example, they found a calcium ion binding to both the MC4R and to the primary molecule that the receptor binds. This instance of the bound calcium ion was a first for Stevens and his group, who have determined the structures of many members of this large class of proteins.
“At first it seemed like more of a scientific curiosity,” says Stevens, who also was a senior author of the study. “But then further experiments revealed that the calcium is actually required for the function of the receptor. Imagine a lock and key situation: in this case, we found that there’s a large key and a small key, and we need both of them to unlock the receptor.”
The research was supported by the National Institutes of Health, the Shanghai Municipal Government, and the GPCR Consortium.
Stevens is the founder of a GPCR structure-based drug discovery company called ShouTi. Cone is a founder of a melanocortin receptor drug discovery company called Courage Therapeutics.
