Study summary · research use only
Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This structural study reports high-resolution cryo-EM structures of the human ghrelin receptor (GHSR)-Gi signaling complex bound to ghrelin and to the non-peptide agonist ibutamoren. Combined with mutagenesis data, the structures show how ghrelin, acylated at Ser3, and ibutamoren bind the receptor, and structural comparison points to a salt bridge and an aromatic cluster near the agonist-binding pocket as motifs associated with receptor activation. The cryo-EM analysis also noted structural variation in how Gi couples to GHSR.
Abstract
The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-Gi signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the Gi and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.
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