CGRP receptor blocker fragment (alpha-CGRP 19-37)
A lab-made piece of the body's own CGRP signaling peptide that plugs into the CGRP receptor without switching it on, blocking the real signal. Used only as a research tool, not a medicine.
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
α-CGRP (19–37) is a 19-amino-acid fragment cut from the C-terminal half of human α-CGRP (calcitonin gene-related peptide), one of the body's own signaling peptides. Unlike the full-length parent — which is a potent vasodilator and is the target of modern migraine drugs — this shortened fragment lacks the N-terminal portion needed to switch the receptor on, and instead behaves as a receptor antagonist (Rovero 1992). It is a laboratory research tool used to probe CGRP-family receptor pharmacology, not a therapeutic.
History
The first systematic characterization of this fragment was published in 1992 by Rovero and colleagues in Peptides, who tested a series of short C-terminal pieces of human αCGRP — including CGRP(19–37) and the shorter CGRP(23–37) — and showed that they retained binding affinity but acted as antagonists of CGRP-evoked responses (Rovero 1992). That finding established the broader principle that the C-terminus of CGRP is the receptor-recognition end of the molecule, while the N-terminus is required for receptor activation.
What it does
The full α-CGRP peptide engages its receptor in two steps: the C-terminal half docks into the receptor's extracellular surface, and the N-terminal half then engages the transmembrane region to switch on signaling (Conner 2007). Because α-CGRP (19–37) keeps only the C-terminal docking half, it can sit in the receptor's binding pocket but cannot trigger the activation step — so it occupies the receptor without firing it, blocking the natural ligand from getting in (Rovero 1992; Conner 2007).
Mechanism
The canonical CGRP receptor is not a single protein but a heterodimer of the calcitonin receptor-like receptor (CLR) — a family B (secretin-like) GPCR — paired with receptor activity-modifying protein 1 (RAMP1) (Hay 2018). The same calcitonin/CGRP peptide family also engages the calcitonin receptor (CTR), which when paired with RAMP1, RAMP2, or RAMP3 gives rise to the amylin receptors AMY₁, AMY₂, and AMY₃ (Hay 2018). The card's stored target calcr refers to the calcitonin receptor (CTR), which sits at this same intersection of CGRP-, amylin-, and calcitonin-family signaling (Barwell 2012).
Structural work on the CGRP receptor has shown that the C-terminus of CGRP contacts the extracellular N-termini of CLR and RAMP1, while the N-terminal residues of CGRP reach down into the transmembrane bundle and the second extracellular loop to drive activation (Conner 2007). Fragments missing the N-terminus — such as CGRP(19–37) — therefore preserve the docking interaction but cannot drive receptor activation, which is the structural basis for their antagonist behavior (Conner 2007; Rovero 1992). Lee and colleagues (2016) extended this picture by mapping how calcitonin-family peptides — including amylin — engage their receptor complexes, providing a comparative view of how peptide N- and C-terminal segments contribute to binding versus activation across the family.
The CGRP receptor family is of broad therapeutic interest: family B GPCRs in this group are implicated in osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine, and cardiovascular disease (Barwell 2012). α-CGRP (19–37) itself is used as a pharmacological tool to dissect those signaling pathways rather than as a clinical candidate.
Evidence
- Human: No clinical trials. This fragment is a research tool.
- Animal / tissue: Antagonist activity against CGRP-evoked responses demonstrated in short-fragment pharmacology studies of human αCGRP (Rovero 1992).
- In vitro / structural: Receptor-binding architecture of CGRP — C-terminal docking, N-terminal activation — characterized in CLR/RAMP1 binding and activation studies (Conner 2007), with cross-family interaction mechanisms mapped for calcitonin- and amylin-receptor complexes (Lee 2016). Pharmacology and nomenclature of the calcitonin/CGRP receptor family reviewed in the IUPHAR Review 25 (Hay 2018) and in a comparative survey of CTR and CLR as family B GPCRs (Barwell 2012).
Known effects
- CGRP-receptor antagonism (in vitro / ex vivo) — Documented for the short C-terminal αCGRP fragments CGRP(19–37) and CGRP(23–37) (Rovero 1992).
- Receptor-pharmacology probe — Used to dissect the contribution of the N-terminal versus C-terminal halves of CGRP to receptor binding and activation, in the context of the broader CLR/CTR + RAMP family (Conner 2007; Hay 2018).
Regulatory status
- US / EU: Not an approved drug. Research-use chemical only.
- WADA: Not specifically listed; clinical CGRP-pathway drugs target the full receptor signaling and are distinct from this research fragment.
Related peptides
- Other entries in the calcitonin/CGRP/amylin peptide family — α-CGRP, β-CGRP, amylin, adrenomedullin, adrenomedullin 2 / intermedin, and calcitonin — share receptor components (CTR or CLR paired with RAMPs) and form a closely linked pharmacological family (Hay 2018).
peptidemodel.com
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 the receptor family member determine the shape this peptide takes when it binds?
If the receptor shapes the peptide rather than the other way around, scientists could fine-tune the fragment to preferentially block one receptor variant linked to migraine while sparing others linked to blood pressure regulation, reducing side effects.
Does this peptide fragment get its grip mainly from the RAMP1 helper protein rather than from the calcitonin receptor?
If true, drug designers targeting migraines would know they must model the RAMP1 partner protein to accurately predict how well blockers like this one work. This could improve the accuracy of computational drug screens for migraine treatments.
Do the two naturally floppy spots in this peptide determine whether it fits into the receptor correctly?
If the hinge residues are confirmed as essential, it would give chemists a clear set of rules for what not to change when redesigning this peptide as a drug, speeding up and de-risking medicinal chemistry programs aimed at migraine treatments.
Would joining the two ends of this floppy fragment together make it bind the receptor more tightly?
If joining the ends works, it could turn a weak research tool into a stronger drug candidate for migraine, and could be made by standard chemistry labs without expensive antibody manufacturing. The size of any gain is unknown until tested.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7324920296669006 | openfold3-mlx |
| ranking score | 0.8363579511642456 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.832 | global PDE — lower = better |
| disorder | 0.233 | fraction disordered |
| chain pair ipTM (A, B) | 0.732 | 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 | 427s |
| 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{pep10654,
sequence = {SGGVVKNNFVPTNVGSKAF},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}