pe
pep-10546 v1 CC-BY-SA-4.0

PTSD and migraine brain-receptor blocker (PACAP-27 fragment 6-27)

A lab-made fragment of a stress-signaling protein that blocks a brain receptor linked to fear, PTSD-like responses, and migraine; used only as a lab research tool.

statusbioassayed targetPAC1R length22 aa refs3
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 4 / 5 · 2 verified on platform
prediction metrics openfold3-mlx 0.3.1
ipTM0.775
pTM0.683
avg pLDDT37.3
ranking score0.852
STRUCTURE · PEP-10546 × PAC1R
ranking0.852
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
openfold3-mlx 0.3.1 · mmCIF ↓ download
sequence22 aa
1510152022
FTDSYSRYRKQ MAVKKYLAAVL
Hypotheses4 directions▾ collapse

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.

openupdated 2026-06-11

Does the peptide grab the receptor surface through an initial electrical attraction before snapping into its final shape?

Understanding exactly how the peptide attaches could let researchers engineer versions that stay bound longer or shorter as needed, which matters for building drugs with the right duration of action for PTSD or migraine treatment.

The hypothesis
Elevated intrinsic disorder in the free form of PACAP-27(6-27) (pLDDT 37.3) reflects a coupled folding-and-binding mechanism at PAC1R in which the charged central cluster (RYRKQMAVK) makes initial electrostatic contact with the negatively charged PAC1R ECD surface, driving a disorder-to-helix transition in the C-terminal KYLAAVL region that locks the complex, consistent with a two-step fly-casting binding model.
Why it’s plausible
The combination of a highly disordered free-peptide ensemble (pLDDT 37.3) with a moderate-to-good predicted complex ipTM (0.775) is the computational signature of coupled folding-and-binding. The RYRKQMAVK stretch contains four cationic residues (R, R, K, K) that could electrostatically preorient toward the acidic PAC1R ECD before the hydrophobic C-terminus docks, a fly-casting mechanism documented for other disordered neuropeptides.
Why it matters
If the binding mechanism is two-step and electrostatic-driven, modulating ionic strength or introducing phosphomimetic residues in the central cluster could fine-tune residence time at PAC1R, offering an engineering handle to optimize on-rate vs. off-rate independently for therapeutic or diagnostic use.
Plausibility.60
Novelty.60
Impact.45
Basis · grounding1 paper · 2 computed/notes
[1]
structurepLDDT=37.3 confirms highly disordered free peptide; ipTM=0.775 confirms ordered complex, diagnostic of coupled folding-and-binding
[2]
sequenceRYRKQMAVK contains 4 basic residues (R7, R8, K9, K16 in fragment numbering) consistent with electrostatic fly-casting against acidic receptor ECD
[3]
paper
PAC1R ECD loop region contributes hydrophobic contacts to ligand binding, the likely landing zone for the C-terminal helix in the second binding step
doi: 10.2174/1568026619666190709092647
openupdated 2026-06-11

Does removing the first five amino acids of PACAP-27 turn a receptor activator into a receptor blocker?

This mirrors how other N-terminally shortened PACAP fragments are already known to bind the receptor without activating it. If it holds for this fragment, it could support development of a PTSD or migraine drug that blocks the overactive receptor instead of switching it on, though that link to disease is still unproven.

The hypothesis
PACAP-27 fragment 6-27 (FTDSYSRYRKQMAVKKYLAAVL) acts as a partial antagonist at PAC1R by retaining the C-terminal helical anchor region (KYLAAVL) needed for receptor docking but lacking the N-terminal HSDGIF activation motif required for full agonism, producing receptor occupancy without downstream cAMP activation.
Why it’s plausible
The parent PACAP-27 N-terminus (His1-Ser2-Asp3-Gly4-Ile5-Phe6) is the canonical activation tip for class B GPCRs; its absence in this fragment mirrors the pharmacology of other truncated VIP/PACAP fragments that bind but fail to activate. The moderate ipTM of 0.775 supports physical docking to PAC1R while the very low pLDDT (37.3) reflects intrinsic disorder, consistent with a fragment that folds only upon receptor engagement.
Why it matters
Confirming partial antagonism would validate this fragment as a selective PAC1R blocker for PTSD and migraine without the off-target agonism that limits full PACAP use as a therapeutic, directly informing its development path.
Plausibility.85
Novelty.20
Impact.55
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceFragment starts at position 6 of PACAP-27, lacking the N-terminal HSDGIF activation tip (His1 critical for class B GPCR activation)
[2]
structureipTM=0.775 indicates moderate-to-good predicted interface with PAC1R; pLDDT=37.3 indicates the free peptide is intrinsically disordered
[3]
paper
125I-PACAP-27 displacement assay at PAC1R splice variants confirms the parent peptide binds the same receptor
doi: 10.1074/jbc.271.29.17267
openupdated 2026-06-11

Would chemically locking the tail of this peptide into a ring make it bind tighter and survive longer in the body?

Helix-locking by cyclization is a proven way to boost peptide stability and binding for related molecules. If it works here, it could turn this short peptide into a more drug-like candidate, though the exact ring chemistry and its effect on this fragment still need testing.

The hypothesis
Cyclization of PACAP-27(6-27) via a lactam bridge between the Lys16 side chain and the C-terminal carboxylate would pre-organize the KYLAAVL amphipathic helix, increase PAC1R binding affinity, and improve proteolytic stability in plasma compared to the linear fragment, without disrupting the disordered central linker needed for initial ECD engagement.
Why it’s plausible
Pre-organizing the C-terminal helix of disordered class B GPCR peptide ligands via lactam stapling consistently increases both receptor affinity and plasma half-life. KYLAAVL occupies positions 17-22 of this fragment; Lys16 is immediately N-terminal to this segment, making a C-terminal lactam geometrically favorable. The central disordered segment would remain free to mediate initial electrostatic contacts.
Why it matters
Linear neuropeptides including PACAP fragments are rapidly degraded by plasma peptidases, making them impractical as drugs. A stabilized, higher-affinity cyclic analogue of this fragment would dramatically improve the drug-likeness of this PAC1R-targeting scaffold for both PTSD and migraine indications.
Plausibility.55
Novelty.40
Impact.55
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceLys16 of the fragment (KYLAAVL motif starts at position 16) provides a primary amine for lactam formation with the C-terminal carboxylate; helix spans 7 residues, optimal for i,i+6 bridge
[2]
structurepLDDT=37.3 in free peptide confirms helix is not pre-formed in solution, suggesting conformational pre-organization via cyclization would pay an entropic benefit upon binding
[3]
paper
Hydrophobic C-terminal region is the primary interface with PAC1R ECD, the segment that would be pre-organized by cyclization
doi: 10.2174/1568026619666190709092647
openupdated 2026-06-11

Is the short hydrophobic tail (KYLAAVL) a major part of what grips the receptor?

If the tail contributes most of the binding, chemists might build a much shorter, cheaper peptide that is easier to deliver to the brain. The central basic stretch likely still adds some binding strength, so it may not be a pure spacer.

The hypothesis
The C-terminal KYLAAVL segment of PACAP-27(6-27) forms a stable amphipathic helix upon PAC1R ECD engagement that is the primary energetic driver of receptor affinity, while the central RYRKQMAVK stretch (residues 8-16 of the fragment) functions mainly as a disordered linker that modulates aqueous solubility rather than contributing direct binding energy.
Why it’s plausible
The very low free-peptide pLDDT (37.3) indicates global disorder in solution. The KYLAAVL motif matches a hydrophobic-face amphipathic helix consensus seen in PACAP/VIP C-termini that nucleate receptor binding. The central lysine-arginine cluster (RYRKQMAVK) likely remains flexible and solvent-exposed, consistent with disordered linker behavior in class B GPCR peptide ligands.
Why it matters
If KYLAAVL is the dominant binding anchor, fragment engineering could shorten the peptide to that core plus a minimal linker, improving metabolic stability and blood-brain barrier penetration for CNS indications.
Plausibility.50
Novelty.45
Impact.50
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceKYLAAVL contains alternating hydrophobic (Y, L, A, V, L) and polar/charged (K) residues consistent with amphipathic helix motif
[2]
structurepLDDT=37.3 indicates the free peptide is globally disordered, suggesting folding is induced by receptor contact
[3]
paper
Hydrophobic interactions between ligand and ECD are a dominant binding contributor in all available PAC1R peptide structures
doi: 10.2174/1568026619666190709092647
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.7746410369873047 openfold3-mlx
ranking score 0.8522644639015198 openfold3-mlx
structural qualityopenfold3
0
metricvaluenote
gpde0.830global PDE — lower = better
disorder0.192fraction disordered
chain pair ipTM (A, B)0.775interface quality
3-letter notation
Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu
recipeopenfold3-mlx 0.3.1
parametervalue
modelopenfold3-mlx 0.3.1
weightsaedd8f3eb814e392…
hardwareapple_m4_base_16gb
mlx version0.31.1
python3.14.3
random seed42
msa strategycolabfold
diffusion samples1
runtime417s
predicted bymlx@peptide
predicted at2026-04-23
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
peptidemodel (2026). PTSD and migraine brain-receptor blocker (PACAP-27 fragment 6-27) (pep-10546, v1). PeptideModel. https://peptidemodel.com/card/pep-10546
@peptide{pep10546,
  sequence = {FTDSYSRYRKQMAVKKYLAAVL},
  target   = {pac1r},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
clinical trials 34 on ct.gov · checked 2026-05-22
ct.gov trials 34
with results 1
PubMed RCT 3
by phase
2phase 11phase 47no phase
by status
6completed1recruiting1active1terminated1unknown
references 3 papers
discussion no comments
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peptidemodel.com CC-BY-SA-4.0 research only · not for human use