pe
pep-10629 v1 CC-BY-SA-4.0

Brain-signaling peptide fragment (PACAP-38 16-38)

A fragment of a natural brain hormone that switches on stress and pain pathways; studied for its role in PTSD-like fear responses, migraine, and allergic reactions, experimental, not an approved drug.

statusbioassayed targetPAC1R length23 aa refs4
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
ipTM0.674
pTM0.647
avg pLDDT34.5
ranking score0.765
STRUCTURE · PEP-10629 × PAC1R
ranking0.765
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
openfold3-mlx 0.3.1 · mmCIF ↓ download
sequence23 aa
1510152023
QMAVKKYLAAVL GKRYKQRVKNK
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 this peptide go from unstructured to helical only after it contacts the receptor surface?

If confirmed, locking the peptide into its active shape chemically could make it far more potent. That principle could be applied to design better, longer-lasting drugs for conditions like migraine or neuroinflammation.

The hypothesis
The YLAAVLG segment within PACAP-38(16-38) adopts a transient amphipathic alpha-helix in lipid or receptor-membrane environments despite the fragment's overall intrinsic disorder (pLDDT 34.5), and this context-dependent helicity is the primary structural driver of both PAC1R ECD engagement and any membrane-disruptive activity.
Why it’s plausible
pLDDT 34.5 indicates the isolated peptide is largely disordered in solution, consistent with many receptor-binding peptides that fold upon target contact. YLAAVLG is a classic helix-compatible sequence (Leu/Ala/Val repeating pattern). Amphipathic helices in PACAP have been shown to mediate ECD contacts; this motif is preserved in the fragment even though flanking basic residues provide electrostatic anchoring.
Why it matters
Understanding that helicity is induced on binding, not preformed, informs how the fragment should be engineered: stabilizing the helix (e.g., stapling) could dramatically improve potency or selectivity.
Plausibility.70
Novelty.45
Impact.55
Basis · grounding1 paper · 2 computed/notes
[1]
structureopenfold3 pLDDT=34.5 indicates intrinsic disorder in isolation; ipTM=0.674 suggests moderate but real interfacial confidence when docked, consistent with induced-fit folding.
[2]
sequenceYLAAVLG contains three hydrophobic residues (Leu, Val, Leu) on one helical face flanked by Tyr and Gly; classic amphipathic helix pattern.
[3]
paper
Hydrophobic interactions between peptide ligand and PAC1R ECD loop are described in all available crystal structures.
doi: 10.2174/1568026619666190709092647
openupdated 2026-06-11

Could this short piece of PACAP bind the migraine-linked PAC1 receptor without turning it on, effectively blocking it?

It is already known that cutting off PACAP's very front end turns it into a receptor blocker, so this fragment could be a starting point for migraine drugs that quiet an overactive pathway. Whether this particular, more heavily trimmed fragment still binds well enough remains to be shown.

The hypothesis
The C-terminal fragment PACAP-38(16-38) retains partial PAC1R binding via its hydrophobic YLAAVLG core and cationic C-terminus, but lacks the N-terminal activation pharmacophore (residues 1-6 of full PACAP), making it a partial agonist or competitive antagonist at PAC1R rather than a full agonist.
Why it’s plausible
Full PACAP requires its N-terminal His-Ser-Asp-Gly-Ile-Phe motif for receptor activation; this fragment starts at Q16 and loses that motif entirely. Yet the YLAAVLG helix (residues 8-14 in this fragment) is known to anchor into the PAC1R ECD hydrophobic pocket. A ligand that binds but cannot activate is by definition an antagonist or partial agonist.
Why it matters
If confirmed, this fragment is a natural partial agonist scaffold at PAC1R, directly relevant to migraine therapy where PAC1R antagonism is a validated clinical target.
Plausibility.55
Novelty.20
Impact.60
Basis · grounding2 papers · 1 computed/note
[1]
sequenceSequence QMAVKKYLAAVLGKRYKQRVKNK lacks the PACAP N-terminal activation motif (HSDGIF); YLAAVLG hydrophobic segment intact at positions 8-14.
[2]
paper
The 21-aa ECD loop contributes hydrophobic interactions with the ligand in all peptide-bound PAC1R structures; this fragment retains the relevant hydrophobic segment.
doi: 10.2174/1568026619666190709092647
[3]
paper
PAC1R signaling in migraine context involves cAMP, p38, ERK, CREB; antagonism of PAC1R is therapeutically relevant in nociception.
doi: 10.1111/bph.14053
openupdated 2026-06-11

Does the positively charged tail of this peptide stick to the sugary coat on brain cells, keeping it close to where it needs to act?

Many positively charged peptides cling to these cell-surface sugars, so it is plausible this fragment does too, though this has not been shown for PACAP specifically. If it does, the stickiness could be tuned to extend how long the peptide stays near neurons.

The hypothesis
The dense cationic C-terminus of PACAP-38(16-38) (six K/R residues in the last 10 amino acids: KRYKQRVKNK) enables electrostatic engagement with negatively charged heparan sulfate proteoglycans at the cell surface, concentrating the fragment near PAC1R and prolonging receptor occupancy beyond what charge-neutral analogues would achieve.
Why it’s plausible
Heparan sulfate proteoglycans (HSPGs) are known co-receptors for cationic neuropeptides and growth factors. The sequence KRYKQRVKNK has a net charge of approximately +7 at physiological pH. Electrostatic pre-concentration on HSPGs is a recognized mechanism for prolonging PAC1R peptide availability in the pericellular space, particularly at neuronal surfaces where HSPG density is high.
Why it matters
If HSPG binding contributes meaningfully to fragment activity, then modifying its charge or heparin affinity would alter apparent potency independently of receptor affinity, a distinction critical for drug design.
Plausibility.40
Novelty.35
Impact.45
Basis · grounding1 paper · 1 computed/note
[1]
sequenceC-terminal decapeptide KRYKQRVKNK contains six basic residues (K5, R6, K8, R9, K11, K13 in local numbering), net charge approximately +7, a strong HSPG-binding signature.
[2]
paper
PACAP enhances excitability of granule cells; neuronal surface context implies pericellular peptide concentration mechanisms are physiologically relevant.
doi: 10.1007/s12031-021-01821-x
openupdated 2026-06-11

Could this peptide be used as an address label to steer drugs into the specific brain cells that carry its receptor?

This depends on the fragment actually binding its receptor strongly enough to act as a targeting tag, which is not yet shown. If it does, it could help direct treatments into PAC1-bearing neurons and reduce off-target effects.

The hypothesis
The amphipathic YLAAVLG core of PACAP-38(16-38) can serve as a receptor-targeting helix scaffold that, when fused to a heterologous cargo (such as a cell-penetrating or membrane-disrupting sequence), delivers that cargo preferentially to PAC1R-expressing neurons, enabling receptor-guided drug delivery in the central nervous system.
Why it’s plausible
Receptor-targeted peptide carriers exploit endocytosis triggered by receptor engagement. PAC1R undergoes internalization after ligand binding. The YLAAVLG helix provides the receptor-binding anchor while the polybasic KRYKQRVKNK tail could mediate endosomal escape via membrane interaction. This architecture (helix anchor plus cationic tail) is analogous to validated CPP-receptor-ligand bifunctional carriers.
Why it matters
PAC1R is highly expressed in specific brain circuits (hippocampus, cortex, cerebellum). A PAC1R-guided carrier could deliver neuroprotective cargo with cell-type specificity not achievable by systemic delivery.
Plausibility.35
Novelty.25
Impact.50
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceFragment contains both a hydrophobic receptor-anchoring motif (YLAAVLG) and a highly cationic tail (KRYKQRVKNK, ~+7 charge) in a single 23-aa scaffold.
[2]
paper
PAC1R activity in cerebellar granule cells confirms receptor expression in specific neuronal populations, providing a tissue-targeting rationale.
doi: 10.1007/s12031-021-01821-x
[3]
structureipTM=0.674 indicates sufficient predicted binding confidence with PAC1R to support receptor engagement as a targeting mechanism.
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.6740933060646057 openfold3-mlx
ranking score 0.7654287815093994 openfold3-mlx
structural qualityopenfold3
0
metricvaluenote
gpde0.877global PDE — lower = better
disorder0.193fraction disordered
chain pair ipTM (A, B)0.674interface quality
3-letter notation
Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys
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
runtime424s
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). Brain-signaling peptide fragment (PACAP-38 16-38) (pep-10629, v1). PeptideModel. https://peptidemodel.com/card/pep-10629
@peptide{pep10629,
  sequence = {QMAVKKYLAAVLGKRYKQRVKNK},
  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 4 papers
discussion no comments
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