Molecular mechanism of agonism and inverse agonism in ghrelin receptor
Open accessAbstract
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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Ghrl's dual role in regulating appetite and energy homeostasis may indirectly influence GH synthesis by reducing feeding behaviors, further exacerbating the effect of chronic social defeat stress.
“Moreover, Ghrl’s dual role in regulating appetite and energy homeostasis may indirectly influence GH synthesis by reducing feeding behaviors, further exacerbating the effect of chronic social defeat stress”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [58]
The Introduction (page unavailable) identifies ghrelin as the endogenous agonist of a receptor involved in appetite regulation and glucose homeostasis, supporting the broad regulatory point. It does not say that ghrelin reduces feeding, indirectly affects GH synthesis through feeding, or exacerbates chronic social defeat stress; searches for those mechanisms returned no supporting passage. (LLM, conf=0.87)
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“Moreover, Ghrl ’s dual role in regulating appetite and energy homeostasis may indirectly influence GH synthesis by reducing feeding behaviors, further exacerbating the effect of chronic social defeat stress [58].”
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BindingDB (2023) · UC San Diego · doi:10.7270/q2930z75
- Authors
- Qin, J., Cai, Y., Xu, Z., Ming, Q., Ji, S.-Y., Wu, C., Zhang, H., Mao, C., Shen, D.-D., Hirata, K., Ma, Y., Yan, W., Zhang, Y., & Shao, Z.
- Affiliations
- Sichuan University (CN)
- Zhejiang University (CN)
- Sir Run Run Shaw Hospital (CN)
- SPring-8 (JP)
- Corresponding author
- Ma, Yanbin
- Yan, Wei
- Zhang, Yan
- Shao, Zhenhua
- ORCID
- Venue
- Nature Communications
- Published
- 2022-01-13
- Volume
- 13
- Issue
- 1
- Pages
- 300-300
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8758724
- OpenAlex
- W4206823974
- Cited by
- 57
- References
- 74
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 12 · 2023: 10 · 2022: 8
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (32100959, 81922071, 31972916)
- Ministry of Education, India
- Department of Science and Technology of Sichuan Province (2020YJ0208)
- Zhejiang University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- growth hormone secretagogue receptor, G protein-coupled receptors, inverse agonism, constitutive activity, ghrelin, receptor activation mechanism, ligand binding modes, hydrophobic clusters, receptor-G protein complex, ligand design
- MeSH terms
- Humans, Ligands, Mutation, Protein Binding, Crystallography, X-Ray, Cryoelectron Microscopy, Ghrelin, Receptors, Ghrelin
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