Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren

Heng Liu,Jean-Louis Baneres,Marjorie Damian,Ji Sun,Dapeng Sun,Cheng Zhang,Alexander Myasnikov

doi:10.1038/s41467-021-26735-5

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.

Highlights

The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling
It mainly signals through the growth hormone secretagogue receptor (GHSR, or ghrelin receptor), a class A G protein-coupled receptor (GPCR)
Ghrelin signaling through GHSR stimulates growth hormone secretion and food intake under nutritional or physiological challenges[1,2]

Summary

Introduction

The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. We showed that mutations of hydrophobic residues in the cavity II to larger or polar residues, which potentially disrupt the binding of the octanoyl moiety, resulted in compromised GHSR signaling induced by ghrelin (Fig. 2c and Supplementary Fig. 3a). Subtle structural differences can be observed at the upper region of the binding pocket including ECL2 and 3 (Supplementary Fig. 3c), likely caused by the binding of Leu5-Val[12] of ghrelin in this region.

Results

Conclusion