Appetite-regulating hormone fragment from the amylin precursor (IAPP [56-74])
A naturally occurring piece of the amylin hormone, released from the pancreas alongside insulin, that activates the calcitonin receptor to help regulate appetite and blood sugar; experimental, not yet an approved drug.
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
Islet amyloid polypeptide precursor [56-74] is a 19-residue fragment spanning the C-terminal portion of the amylin (IAPP) precursor protein. Amylin is a peptide hormone released alongside insulin from the beta cells of the pancreas after meals, and it plays a well-established role in controlling appetite and blood glucose. This fragment was detected directly in pancreatic islet extracts by mass spectrometry-based peptidomics (Boonen and colleagues 2007), as a C-terminally amidated peptide, which marks it as a genuine processing product of the amylin precursor rather than a degradation artefact. Its sequence carries proline substitutions at positions corresponding to human amylin residues 25, 28, and 29 — the same pattern found in rat amylin and in the clinically approved analog pramlintide — which prevents the aggregation that human amylin can undergo. The stored sequence SSNNLGPVLPPTNVGSNTY does not include the C-terminal amide modification; the biologically relevant form carries a –NH₂ cap on the final tyrosine, installed by the peptidyl amidating monooxygenase complex (PAM) during processing.
History
Amylin itself was identified in the late 1980s by Cooper and colleagues as the major protein component of amyloid deposits in the pancreatic islets of type 2 diabetes patients, and named islet amyloid polypeptide (IAPP). Its role as a hormone — not merely a pathological aggregate — was established shortly after. The broader family it belongs to (calcitonin, calcitonin gene-related peptide, adrenomedullin, and amylin) all act through class B GPCRs related to the calcitonin receptor (Pondel 2000). The specific fragment captured in this card was catalogued by Boonen and colleagues (2007) during a peptidomics survey of neuropeptides in the islets of Langerhans, using liquid chromatography and mass spectrometry to profile the in vivo peptide landscape of pancreatic tissue.
What it does
As the C-terminal domain of mature amylin, this fragment encompasses the region responsible for engaging the extracellular domain (ECD) of the calcitonin receptor (CALCR) and its receptor activity-modifying protein (RAMP) partners. The C-terminal tail of amylin makes direct contact with the CALCR ECD — structural and biochemical studies of the amylin receptor family show that approximately the last 11 residues of the mature peptide anchor the ligand to the receptor's extracellular stalk before the N-terminal helix engages the transmembrane bundle for activation. Within the amylin family, the three amylin receptor subtypes — AMY1R, AMY2R, and AMY3R — each pair the calcitonin receptor core with a different receptor activity-modifying protein (RAMP1, RAMP2, or RAMP3, respectively), which together fine-tune ligand selectivity and signaling bias. The proline substitutions in this fragment's sequence are functionally important: they break helical structure and prevent β-sheet stacking, which is why rat amylin (sharing this proline pattern) does not form the toxic amyloid fibrils that contribute to beta-cell loss in human type 2 diabetes.
Evidence
- Human: No clinical or human tissue data for this specific 19-residue fragment. Its parent hormone amylin is absent in type 1 diabetes and severely depleted in long-standing type 2 diabetes. Pramlintide — a synthetic analog sharing the proline-substituted sequence pattern — is FDA-approved as an adjunct to insulin therapy for both type 1 and type 2 diabetes (approved 2005).
- Animal: This fragment's sequence matches the C-terminal region of rat amylin, which does not aggregate and has been used extensively in rodent studies of amylin physiology. Rat amylin activates the calcitonin receptor and amylin receptor complexes and suppresses food intake via the area postrema and nucleus of the solitary tract in animal models.
- In vitro: The peptide was identified as a C-terminally amidated species in pancreatic islet extract by mass spectrometry (Boonen and colleagues 2007), consistent with enzymatic processing of the proIAPP precursor rather than non-specific degradation.
Known effects
- Calcitonin receptor (CALCR) engagement — C-terminal amylin peptides bind the extracellular domain of CALCR; full-length activity established, fragment-specific binding not independently quantified
- Non-amyloidogenic sequence — proline pattern at positions 25/28/29 prevents β-sheet aggregation; preclinical and analog data
- Amylin receptor context (AMY1R/AMY2R/AMY3R) — C-terminal region of amylin contributes to receptor subtype selectivity; mechanistic, from receptor biochemistry studies
Regulatory status
- US: This fragment itself has no regulatory status. Its parent analog pramlintide (Symlin) is FDA-approved for use with insulin in type 1 and type 2 diabetes. Cagrilintide — a long-acting amylin analog that also activates CALCR — has been submitted for FDA review as part of the CagriSema (cagrilintide + semaglutide) combination; as of June 2026 it is not approved.
- WADA: Amylin analogs are not currently listed on the WADA prohibited list.
Mechanism
Amylin and its C-terminal fragments engage a class B (secretin-family) GPCR receptor architecture. The calcitonin receptor (CALCR, gene name CALCR) is the core subunit; its association with RAMP1, RAMP2, or RAMP3 generates AMY1R, AMY2R, and AMY3R, respectively, each with a distinct pharmacological profile. Binding of the peptide to the receptor ECD — mediated largely by the C-terminal ~11 residues — triggers Gαs-coupled signaling and elevation of intracellular cAMP, with additional PKC-linked cascades (Pondel 2000). In the brain, AMY1R and AMY3R in the area postrema and nucleus of the solitary tract are the primary sites for amylin's satiety and gastric-emptying effects. The proline residues in this fragment's sequence (at positions equivalent to human amylin 25, 28, 29) impose conformational constraints that block the amyloidogenic β-sheet conformation while preserving receptor engagement geometry — the pharmacological basis for pramlintide's design and for the clinical tolerability of rat-type amylin analogs.
Related peptides
- Amylin / IAPP (full-length, human) — the 37-residue hormone this fragment is derived from; see also pramlintide for the pharmacologically active proline-substituted analog
- Calcitonin — shares the CALCR target; the founding ligand of this receptor family (card not yet linked)
- Cagrilintide — long-acting acylated amylin analog under clinical development; activates the same CALCR/amylin receptor axis for weight management
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.6908061504364014 | openfold3-mlx |
| ranking score | 0.8056010007858276 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.866 | global PDE — lower = better |
| disorder | 0.239 | fraction disordered |
| chain pair ipTM (A, B) | 0.691 | 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 | 428s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
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{pep10660,
sequence = {SSNNLGPVLPPTNVGSNTY},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}