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

AbstractThe 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.

Download Full-text

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

10.21203/rs.3.rs-646701/v1 ◽

2021 ◽

Author(s):

Cheng Zhang ◽

Heng Liu ◽

Dapeng Sun ◽

Alexander Myasnikov ◽

Marjorie Damian ◽

...

Keyword(s):

Growth Hormone ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Salt Bridge ◽

Binding Pocket ◽

Binding Mode ◽

Receptor Activation ◽

Structural Basis ◽

Ghrelin Receptor ◽

Signaling Complex

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. The structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable variations of the Gi binding mode are observed in our cryo-EM analysis, indicating the highly dynamic nature of Gi-coupling to GHSR. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.

Download Full-text

Echinacoside Isolated from Cistanche tubulosa Putatively Stimulates Growth Hormone Secretion via Activation of the Ghrelin Receptor

Molecules ◽

10.3390/molecules24040720 ◽

2019 ◽

Vol 24 (4) ◽

pp. 720 ◽

Cited By ~ 6

Author(s):

Chieh-Ju Wu ◽

Mei-Yin Chien ◽

Nan-Hei Lin ◽

Yi-Chiao Lin ◽

Wen-Ying Chen ◽

...

Keyword(s):

Growth Hormone ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Major Constituent ◽

Pituitary Cells ◽

Significant Activity ◽

Aging Effects ◽

Phenylethanoid Glycosides ◽

Ghrelin Receptor ◽

Cistanche Tubulosa

Cistanche species, the ginseng of the desert, has been recorded to possess many biological activities in traditional Chinese pharmacopoeia and has been used as an anti-aging medicine. Three phenylethanoid glycosides—echinacoside, tubuloside A, and acteoside—were detected in the water extract of Cistanche tubulosa (Schenk) R. Wight and the major constituent, echinacoside, was further purified. Echinacoside of a concentration higher than 10−6 M displayed significant activity to stimulate growth hormone secretion of rat pituitary cells. Similar to growth hormone-releasing hormone-6, a synthetic analog of ghrelin, the stimulation of growth hormone secretion by echinacoside was inhibited by [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Molecular modeling showed that all the three phenylethanoid glycosides adequately interacted with the binding pocket of the ghrelin receptor, and echinacoside displayed a slightly better interaction with the receptor than tubuloside A and acteoside. The results suggest that phenylethanoid glycosides, particularly echinacoside, are active constituents putatively responsible for the anti-aging effects of C. tubulosa and may be considered to develop as non-peptidyl analogues of ghrelin.

Download Full-text