Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor

Wang, Yue; Guo, Shimeng; Zhuang, Yahui; Yu, Ying; Xu, Peiyu; He, Xinheng; Guo, Jia; Yin, Wanchao; Xu, Hao; Xie, Xin; Jiang, Yi

doi:10.1038/s41467-021-25364-2

Cited by 54 publications

(90 citation statements)

References 42 publications

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“…3c ), suggesting that the polar interactions of E124 3.33 , R283 6.55 , S217 5.43 , and N305 7.35 in the receptor and Gly +1 and Ser +2 in the ghrelin peptide play significant roles in receptor activation. In accordance with previously published Gq-coupled ghrelin receptors in complex with ghrelin structure 39 , Gly +1 and Ser +2 in ghrelin are engaged in similar contacts with receptors (Supplementary Fig. 8b ).…”

Section: Resultssupporting

confidence: 91%

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Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Qin

Cai

et al. 2022

Nat Commun

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Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.

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Section: Resultssupporting

confidence: 91%

“…When our manuscript was under review, another study about the Gq-coupled ghrelin receptor was published, and it reported the structure of the ghrelin-bound receptor complex 39 . Obviously, Gly +1 and Ser +2 of ghrelin inserted into the same orthosteric site of the receptor, whether binding to either Go or Gq.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Qin

Cai

et al. 2022

Nat Commun

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“…At present, studies have found that ghrelin can also play a certain role in the treatment of cardiovascular diseases, including regulating sympathetic nerve activity and hypertension, enhancing vascular activity and angiogenesis, inhibiting arrhythmia, reducing heart failure, and inhibiting cardiac remodeling after myocardial infarction [ 4 ] . The cardiovascular protective effect of ghrelin may be related to anti-inflammatory, antiapoptosis, inhibition of sympathetic nerve activation, regulation of autophagy, and endothelial dysfunction [ 5 ]. However, the relationship between ghrelin and the cardiovascular system has not been elaborated in the relevant literature; so, it is very important to further explore the pharmacology of ghrelin to regulate and treat cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Zhao

Sun

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To study the possible mechanism of ghrelin in heart failure and how it works. Method. In vitro results demonstrated that ghrelin alleviates cardiac function and reduces myocardial fibrosis in rats with heart failure. Moreover, ghrelin intervention increased PTEN expression level and reduced ERK, c-jun, and c-Fos expression level; in vivo experiments demonstrated that ghrelin intervention reduces mast memory expression and increases cardiomyocyte surface area, PTEN expression level, ERK, c-jun, c-Fos expression level, and cell surface area, while ERK blockade suppresses mast gene expression and reduces cell surface area. Results. In vitro experimental results prove that we have successfully constructed a rat model related to heart failure, and ghrelin can alleviate the heart function of heart failure rats and reduce myocardial fibrosis. In addition, ghrelin is closely related to the decrease of the expression levels of ERK, c-jun, and c-Fos, but it can also increase the expression of PTEN in the rat model; in vivo experiments proved that we successfully constructed an in vitro cardiac hypertrophy model, and the intervention of ghrelin would reduce the expression of hypertrophic memory and increase the surface area of cardiomyocytes, increase the expression level of PTEN, and reduce the expression levels of ERK, c-jun, and c-Fos, while the blockade of PTEN will increase the expression of hypertrophy genes and increase the cell surface area, while the blockade of ERK will increase the expression of hypertrophic genes, which in turn will make the cell surface area reducing. Conclusion. Ghrelin inhibits the phosphorylation and nuclear entry of ERK by activating PTEN, thereby controlling the transcription of hypertrophic genes, improving myocardial hypertrophy, and enhancing cardiac function.

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“…In another study, the analysis of cryo-electron microscopy structures of ghrelin and the peptide agonist GHRP-6 ( 2 ) in complex with Gq-coupled GHS-R1a has revealed a unique binding pocket for the octanoyl group of AG, which favors its correct positioning to activate the receptor ( Figure 4 ). 16 …”

Section: Structure Of Ghs-r1amentioning

confidence: 99%

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

et al. 2022

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Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

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Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor

Cited by 54 publications

References 42 publications

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

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