How Ghrelin's Unique Acylation Activates Its Receptor: A Structural Insight

Ghrelin, often called "the hunger hormone," is a crucial gastric peptide hormone that profoundly regulates food intake, body weight, and even influences taste sensation, reward pathways, cognition, learning, and memory. A distinctive feature of ghrelin is its acylation, primarily with an octanoic acid group, which is absolutely essential for its ability to bind to and activate the ghrelin receptor, a vital G protein-coupled receptor (GPCR). Given ghrelin's diverse physiological roles, its receptor is an exceptionally attractive drug target for conditions such as growth retardation, obesity, and various metabolic disorders. Despite its importance, the precise molecular mechanisms governing how this unique acylated ghrelin binds to and activates its receptor at an atomic level remained largely unknown.

The cryo-EM structures provided remarkable detail, revealing a unique and previously uncharacterized binding pocket specifically designed to accommodate the octanoyl group of ghrelin. This pocket was shown to be critical, as it precisely guides the correct three-dimensional positioning of the peptide within the receptor, which is the initial and essential step for initiating receptor activation. The most significant finding was the identification of a distinct binding site for the octanoyl moiety, demonstrating its indispensable role in orienting the ghrelin peptide for productive engagement and subsequent activation of the ghrelin receptor. Furthermore, the combined mutational and functional data strongly corroborated these structural observations, precisely defining the specific amino acid residues involved in the recognition of the acylated peptide hormone and the subsequent conformational changes that lead to the activation of the ghrelin receptor. These findings offer an atomic-level blueprint of this crucial interaction.