An international team of scientists has found the precise shape of a key player in human metabolism, which could lead the way to better treatments for obesity and other metabolic disease.

For the study, the scientists focused on a protein in the brain, the melanocortin 4 receptor (or 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.
The results are set to appear in the journal Science.

Severe obesity is often linked to other health issues. Recent data on coronavirus have shown that adults 65 and older who are severely obese are among the hardest hit by the illness, according to the Centers for Disease Control and Prevention.

The team began to tackle the MC4R structure, they discovered that four drugs have been developed to target melanocortin receptors in humans. 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.

The authors report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte–stimulating hormone at the MC4R by 37- and 600-fold, respectively.

The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)–independent mechanism for this signaling.

https://news.usc.edu/169128/obesity-treatment-gene-mutation-mc4r-protein-structure-usc-research/

https://science.sciencemag.org/content/368/6489/428