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

Heng Liu, Dapeng Sun, Alexander Myasnikov, Marjorie Damian, Jean-Louis Baneres, Ji Sun () and Cheng Zhang ()
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Heng Liu: University of Pittsburgh
Dapeng Sun: University of Pittsburgh
Alexander Myasnikov: St. Jude Children’s Research Hospital
Marjorie Damian: Université de Montpellier, ENSCM
Jean-Louis Baneres: Université de Montpellier, ENSCM
Ji Sun: St. Jude Children’s Research Hospital
Cheng Zhang: University of Pittsburgh

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26735-5

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