Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.
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The discovery of the precise shape of a brain protein could lead to more-effective drugs for obesity.
A team co-led by scientists at ShanghaiTech University solved the atomic structure of the melanocortin-4 receptor (MC4R), a protein found in the brain that regulates hunger cues and the body’s energy balance.
Unexpectedly, the researchers identified a binding site for calcium on MC4R — a feature not seen with other proteins in the melanocortin receptor family. The team further detailed how calcium binding impacts the affinity of MC4R for neuropeptides that influence downstream signalling.
A drug that activates MC4R is already available for people with rare genetic forms of syndromic obesity, but it is not potent enough to treat more-common, diet-associated forms of obesity. The new structural insights into MC4R could open the door to novel drug designs that can help manage weight problems more broadly.
- Science 368, 428–433 (2020). doi: 10.1126/science.aaz8995