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.
First high-resolution ghrelin receptor structuresCryo-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
What the researchers found
High-resolution cryo-EM structures revealed the molecular basis of ghrelin and ibutamoren binding to GHSR, identifying key activation motifs.
Why it 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 numbers in context
2 cryo-EM structures; GHSR-Gi complex; ghrelin requires Ser3 acylation; salt bridge + aromatic cluster activation motifs
How the study worked
Cryo-electron microscopy of GHSR-Gi signaling complexes with ghrelin and ibutamoren. Combined with mutagenesis experiments to validate binding interactions.
Who was studied
N/A (purified receptor complexes)
What this study cannot tell us
Structures captured in one signaling state (Gi-coupled). Receptor behavior in cell membranes may differ. Ibutamoren is investigational and not approved.
How to read the evidence
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.
When this study was published
Published in 2021, these structures remain the foundational reference for ghrelin receptor pharmacology and continue to guide drug design efforts targeting this receptor.
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.
Questions still open
- 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?
Common questions
What is the ghrelin receptor and why does its structure matter?
What is ibutamoren?
Read the original research
Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.
Nature communications, 12(1), 6410
Citation
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