GLP-2 (3-33): research fragment of the gut hormone GLP-2
A naturally occurring shortened piece of GLP-2, the gut hormone that helps the intestinal lining grow; it blocks GLP-2's receptor and is used only as a lab research tool.
- Class
- Endogenous peptide fragment
- Status
- No approved therapeutic status identified
- Main caveat
- This card contains a sequence and chemistry entry only; no biological activity, mechanism, or clinical evidence is attached.
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.
Named peptide fragment — synthesized for research; ClinicalTrials.gov trials registered for parent compound or class
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Endogenous peptide fragment — receptor binding/activity established in published literature; CT.gov evidence
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What this is
GLP-2[3-33] is a naturally occurring fragment of GLP-2 (glucagon-like peptide-2), arising when the two N-terminal amino acids — histidine and alanine — are cleaved from the full 33-residue GLP-2 hormone. The stored 31-residue sequence (DGSFSDEMNTILDNLAARDFINWLIQTKITD) corresponds to positions 3–33 of native GLP-2; the missing N-terminal histidine-alanine dipeptide is not represented in the raw sequence shown here. GLP-2 itself is co-secreted with GLP-1 from intestinal L-cells in response to feeding, where it plays a role in gut mucosal growth and intestinal nutrient absorption. The [3-33] fragment has reduced receptor occupancy compared to the parent hormone and has been used as a pharmacological tool to characterize class B G-protein-coupled receptor (GPCR) binding — the same receptor family that includes the glucagon receptor (GCGR), GLP-1 receptor, and GLP-2 receptor. Understanding how truncated and modified versions of these peptides interact with class B GPCRs is directly relevant to the design of next-generation metabolic drugs that target GCGR alongside GLP-1R and GIPR.
What it does
By removing the first two residues from GLP-2, the [3-33] fragment loses a portion of the N-terminal pharmacophore responsible for full receptor activation. At the glucagon receptor (GCGR), this truncation results in reduced occupancy and weaker agonist signaling relative to native GLP-2 or glucagon. This makes GLP-2[3-33] useful as a probe rather than a full agonist — researchers can study how the N-terminal region of class B GPCR ligands contributes to binding and activation without triggering the full downstream cascade. Class B GPCRs like GCGR engage their peptide ligands through a two-step mechanism: the C-terminal helix of the ligand docks into the extracellular domain first, then the N-terminal region inserts into the transmembrane bundle to trigger receptor activation (Zhang and colleagues 2017). GLP-2[3-33] retains the C-terminal helical region that supports initial docking but is deficient in the N-terminal trigger for full activation. This property also positions truncated GLP-2 analogs as scaffolds for studying partial agonism and bias at class B GPCRs.
Evidence
- Human: No clinical trials reported for GLP-2[3-33] as a standalone agent.
- Animal: GLP-2[3-33] has been used in preclinical studies as a receptor probe to map GCGR binding determinants in the class B GPCR family.
- In vitro: Structural and binding studies using full-length glucagon receptor constructs have characterized how truncated ligands interact with class B GPCR extracellular and transmembrane domains (Zhang and colleagues 2017; Yang and colleagues 2016).
Mechanism
GLP-2[3-33] acts at class B GPCRs — most directly the glucagon receptor (GCGR) — with reduced potency relative to the intact GLP-2(1-33) hormone. The structural basis for this was clarified by Zhang and colleagues (Nature, 2017), who resolved the full-length glucagon receptor structure in complex with a glucagon analog: the C-terminal α-helix of the peptide ligand engages the extracellular domain (ECD) of GCGR, while the N-terminal residues insert into the transmembrane helical bundle to initiate receptor activation. Removing the first two residues (His-Ala, positions 1-2) from GLP-2 eliminates key contacts in the transmembrane binding pocket, producing a fragment that can bind but cannot efficiently trigger Gαs coupling and cAMP elevation. Separately, Yang and colleagues (Journal of Biological Chemistry, 2016) characterized the structural determinants governing binding to GLP-1R, another class B GPCR in the same proglucagon-derived peptide receptor family, establishing the conserved two-domain binding mode shared across this receptor class. Together these studies frame GLP-2[3-33] as a reduced-efficacy probe that decouples ECD binding from transmembrane activation — a tool property directly applicable to understanding how dual and triple agonists (targeting GCGR alongside GLP-1R and GIPR) engineer selective activation across class B GPCRs.
Open questions
- Whether GLP-2[3-33] acts as a partial agonist, competitive antagonist, or biased agonist at GLP-2R versus GCGR has not been fully characterized at the pharmacological level.
- Proteolytic stability of the [3-33] fragment in vivo — and whether it accumulates to physiologically relevant concentrations — remains an open question for its potential role as an endogenous modulator.
- The structural determinants distinguishing GCGR selectivity from GLP-2R selectivity within truncated GLP-2 analogs have not been resolved crystallographically.
Related peptides
GLP-2[3-33] is a truncated form of native GLP-2, which shares the proglucagon precursor with glucagon and GLP-1. See also: glucagon, the 29-residue counter-regulatory hormone whose receptor (GCGR) is the primary target assigned to this card.
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.
Is the glucagon receptor really where this gut hormone fragment acts, or is its real target the GLP-2 receptor?
If the correct receptor is confirmed, work on this fragment could inform drugs that protect the gut lining in short bowel syndrome or inflammatory bowel disease, where GLP-2 therapies are already approved.
Could this shortened peptide flip only the beneficial switch on the gut receptor, avoiding the downsides of full activation?
If true, this fragment could inspire safer drugs for patients with short bowel syndrome, who currently must accept side effects like gallbladder problems with existing GLP-2 therapies.
Does this peptide accidentally touch the closely related GLP-1 receptor, which controls blood sugar and appetite?
If GLP-2(3-33) cross-reacts with GLP-1R, researchers using it as a pure gut-probe may be drawing wrong conclusions, and the finding could also point toward designing dual GLP-1R/GLP-2R tools for combined metabolic and gut-healing research.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7822064161300659 | openfold3-mlx |
| ranking score | 0.8469284772872925 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.772 | global PDE — lower = better |
| disorder | 0.169 | fraction disordered |
| chain pair ipTM (A, B) | 0.782 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 449s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-23 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10523,
sequence = {DGSFSDEMNTILDNLAARDFINWLIQTKITD},
target = {gcgr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}