First High-Resolution Images Reveal How Ghrelin and Ibutamoren Activate the Hunger Receptor
Cryo-EM structures of the human ghrelin receptor bound to both ghrelin and the synthetic agonist ibutamoren reveal key molecular features needed for receptor activation, providing a blueprint for designing new appetite and growth hormone drugs.
Quick Facts
What This Study Found
High-resolution cryo-EM structures revealed the molecular basis of ghrelin and ibutamoren binding to GHSR, identifying key activation motifs.
Key Numbers
2 cryo-EM structures; GHSR-Gi complex; ghrelin requires Ser3 acylation; salt bridge + aromatic cluster activation motifs
How They Did This
Cryo-electron microscopy of GHSR-Gi signaling complexes with ghrelin and ibutamoren. Combined with mutagenesis experiments to validate binding interactions.
Why This Research Matters
Knowing the exact shape of receptor-drug interactions speeds up the design of better, more selective drugs for appetite disorders and growth hormone conditions.
The Bigger Picture
The ghrelin receptor (GHSR) is a major drug target for obesity, cachexia, and growth hormone disorders, but drug development has been hampered by limited structural understanding. These first high-resolution structures change that — they reveal not only how ghrelin activates the receptor, but also how a non-peptide drug candidate (ibutamoren) binds at a different site. This structural information is invaluable for rational drug design and could accelerate development of selective GHSR modulators. The Gi coupling details also advance understanding of how this GPCR signals differently from related receptors.
What This Study Doesn't Tell Us
Structures captured in one signaling state (Gi-coupled). Receptor behavior in cell membranes may differ. Ibutamoren is investigational and not approved.
Questions This Raises
- ?Could these structures enable the design of biased GHSR agonists that activate appetite but not growth hormone release (or vice versa)?
- ?How does the GHSR structure compare in its constitutively active state versus the agonist-bound states shown here?
- ?Can the ibutamoren binding site be optimized to create more potent or selective non-peptide GHSR agonists?
Trust & Context
- Key Stat:
- First high-resolution ghrelin receptor structures Cryo-EM captured the GHSR-Gi signaling complex with both the natural peptide hormone ghrelin and synthetic agonist ibutamoren, revealing the molecular basis for receptor activation
- Evidence Grade:
- Published in Nature Communications, this is a high-quality structural biology study using state-of-the-art cryo-EM with mutagenesis validation. The structures provide definitive molecular insights, though they represent specific signaling states that may not capture the full range of receptor behaviors.
- Study Age:
- Published in 2021, these structures remain the foundational reference for ghrelin receptor pharmacology and continue to guide drug design efforts targeting this receptor.
- Original Title:
- Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.
- Published In:
- Nature communications, 12(1), 6410 (2021)
- Authors:
- Liu, Heng, Sun, Dapeng, Myasnikov, Alexander, Damian, Marjorie, Baneres, Jean-Louis, Sun, Ji, Zhang, Cheng
- Database ID:
- RPEP-05559
Evidence Hierarchy
Frequently Asked Questions
What is the ghrelin receptor and why does its structure matter?
The ghrelin receptor (GHSR) is the molecular switch that the hunger hormone ghrelin activates to stimulate appetite, growth hormone release, and reward signaling in the brain. Knowing its exact 3D structure — how ghrelin fits into it and triggers activation — is like having the blueprint for a lock. Drug designers can use this to create better 'keys' (drugs) that precisely activate or block the receptor for treating obesity, wasting diseases, and growth hormone disorders.
What is ibutamoren?
Ibutamoren (MK-677) is a synthetic, non-peptide compound that activates the ghrelin receptor to stimulate growth hormone secretion. Unlike ghrelin, which must be injected, ibutamoren can be taken orally. It is currently an investigational drug being studied for growth hormone deficiency and muscle wasting. This study reveals exactly how it binds to the ghrelin receptor, which could help design improved versions.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-05559APA
Liu, Heng; Sun, Dapeng; Myasnikov, Alexander; Damian, Marjorie; Baneres, Jean-Louis; Sun, Ji; Zhang, Cheng. (2021). Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.. Nature communications, 12(1), 6410. https://doi.org/10.1038/s41467-021-26735-5
MLA
Liu, Heng, et al. "Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.." Nature communications, 2021. https://doi.org/10.1038/s41467-021-26735-5
RethinkPeptides
RethinkPeptides Research Database. "Structural basis of human ghrelin receptor signaling by ghre..." RPEP-05559. Retrieved from https://rethinkpeptides.com/research/liu-2021-structural-basis-of-human
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Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.