Glucagon tail fragment: lab tool for studying liver calcium (19-29)
An 11-amino-acid piece of the glucagon hormone that blocks certain liver enzymes involved in calcium handling; used only as a lab research tool.
- Class
- Peptide hormone (pancreatic alpha-cell counter-regulatory hormone)
- Status
- FDA-approved prescription drug (GlucaGen, Baqsimi, Gvoke) for emergency treatment of severe hypoglycemia and diagnostic GI imaging. Approved by EMA, MHRA, Health Canada, and TGA for the same emergency indication.
- Best-supported effect
- Rapid blood glucose elevation in severe hypoglycemia rescue in insulin-treated patients (decades of clinical use, multiple approved formulations); with supporting approved use for smooth-muscle relaxation during diagnostic GI imaging.
- Main caveat
- Native single-dose glucagon does not produce weight loss. Weight-loss effects attributed to "glucagon" derive from dual and triple receptor agonists (survodutide, retatrutide, mazdutide) — separate molecules. Rescue glucagon also fails when hepatic glycogen stores are depleted.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Glucagon (19-29) is the C-terminal eleven-residue fragment (sequence AQDFVQWLMNT) of the full 29-amino-acid glucagon hormone. While full-length glucagon is primarily known as an emergency treatment for severe hypoglycemia, this fragment represents a different pharmacological tool: it has been studied for its ability to inhibit liver ATPase activity and Ca²⁺ transport in hepatic tissue, effects that do not depend on the same N-terminal activation domain through which full-length glucagon stimulates glycogenolysis. Because it retains the C-terminal region of glucagon — the portion most conserved across the glucagon/GLP-1/GIP peptide family — it has also served as a structural reference point in the design of dual and triple receptor agonists. The sequence is identical across human, rat, and porcine glucagon, hence the "(human, rat, porcine)" designation.
What it does
Glucagon (19-29) binds to the glucagon receptor (GCGR), a Class B GPCR expressed on hepatocytes and other tissues, but does so through a binding mode that diverges from the full-length hormone. Rather than triggering the strong cAMP-mediated glycogenolytic response that full-length glucagon produces, the fragment has been associated with inhibitory effects on hepatic ATPase and Ca²⁺ transport. This makes it useful as a biochemical probe: researchers can use it to distinguish the receptor occupancy effects attributable to the C-terminal glucagon domain from those driven by the N-terminal activation domain. In the context of analog design, the C-terminal region of glucagon — which AQDFVQWLMNT represents — is one of the conserved structural elements that structural chemists retain or modify when building GLP-1/glucagon dual agonists, because it contributes to GCGR binding affinity while the GLP-1 N-terminal domain drives receptor activation (Ding and colleagues 2020).
Evidence
- Human: No human clinical data for glucagon (19-29) as an isolated compound. The fragment has not been evaluated in registered clinical trials.
- Animal / cell: Hepatic inhibition of ATPase activity and Ca²⁺ transport has been characterized in liver tissue models. The fragment appears in preclinical glucagon analog tables alongside modified sequences designed for dual and triple receptor agonism (Frontiers in Endocrinology 2021).
- In vitro: The C-terminal glucagon region including AQDFVQWLMNT has been used as a reference sequence in comparative peptide structure–activity relationship work, particularly in studies examining how non-proteinogenic amino acid substitutions affect dual GLP-1/glucagon receptor agonism (Ding and colleagues 2020).
Mechanism
Full-length glucagon binds GCGR in two stages: the C-terminal helix docks in the receptor's extracellular domain to anchor the peptide, then the N-terminal His-Ser residues insert into the transmembrane bundle to trigger Gαs activation, cAMP production, and downstream PKA-mediated glycogenolysis. Glucagon (19-29) — lacking the N-terminal activation domain — retains the C-terminal docking region but cannot initiate the canonical activation cascade in the same way. The fragment's inhibitory activity on liver ATPase and Ca²⁺ transport reflects a distinct receptor-interaction profile, making it a tool for probing Class B GPCR pharmacology at the GCGR without the confounding signal of full glycogenolytic activation.
The full 29-residue glucagon sequence is HSQGTFTSDYSKYLDSRRAQDFVQWLMNT, where AQDFVQWLMNT occupies positions 19–29. This C-terminal region is also the part most directly relevant to the "third-class agonism" concept in GCGR pharmacology — a binding mode in which receptor occupancy at the extracellular domain produces signaling that differs qualitatively from classical N-terminal-dependent activation.
Related peptides
- Full-length glucagon — the complete 29-residue hormone from which this fragment is derived; FDA-approved for emergency hypoglycemia rescue
- Glucagon (1-21) — the complementary N-terminal fragment retaining the activation domain; compare to understand the division of function along the glucagon backbone
- Oxyntomodulin — an endogenous proglucagon-derived peptide that includes the full glucagon sequence plus an 8-residue C-terminal extension; the C-terminal glucagon region in this fragment overlaps with the oxyntomodulin pharmacophore
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does this 11-amino-acid piece of glucagon sit in the receptor and block the full hormone, rather than triggering a response itself?
If true, this fragment could be a starting point for drugs that prevent blood-sugar spikes caused by excess glucagon, helping people with type-2 diabetes without the side effects of full receptor shutdown.
Could this fragment reduce the calcium-driven cell death that damages transplanted livers during surgery, without the blood-sugar side effects of full glucagon?
If true, this could improve outcomes for liver transplant patients by adding a simple, short peptide to organ preservation solutions, protecting the donated liver before and during surgery.
Does this small 11-piece fragment latch onto not just the glucagon receptor but also the GLP-1 receptor, which is the target of Ozempic-class drugs?
If true, this fragment could be the smallest known scaffold capable of engaging both receptors at once, potentially simplifying the design of next-generation weight-loss and diabetes drugs.
If we swap one building block in this fragment, could it bind the glucagon receptor more tightly while still not turning it on?
If true, this could rapidly produce a more effective glucagon-blocking drug candidate for type-2 diabetes, using a very simple chemical change to a naturally occurring fragment.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9714738130569458 | boltz-2 |
| ranking score | 0.8306590914726257 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.512 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10497,
sequence = {AQDFVQWLMNT},
target = {gcgr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}