Abstract
Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.
Highlights
Ghrelin, called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory
We reported two cryo-electron microscopy structures of the active ghrelin receptor–Gq complexes bound to ghrelin and GHRP-6, respectively
Collectively, this study reveals the structural basis for recognition of ghrelin and GHRP-6 by ghrelin receptor and identifies the binding site for the octanoyl group of ghrelin
Summary
Called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. We present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. 1234567890():,; Food intake is one of the most fundamental processes required for sustaining human life It is primarily regulated by two endogenous hormones with opposite physiological functions: leptin, the energy surfeit hormone, and ghrelin, the hunger hormone, both of which are involved in controlling energy balance and obesity. We reported two cryo-electron microscopy (cryo-EM) structures of the active ghrelin receptor–Gq complexes bound to ghrelin and GHRP-6, respectively
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