pe
pep-05449 v1 CC-BY-SA-4.0

CRSP1 opioid receptor signaling peptide

A brain-made chemical messenger designed to act on opioid receptors, the same body system that controls pain and mood; experimental, not an approved medicine.

statusbioassayed targetOPRM1 length46 aa refs1
neuropeptide
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 2 / 5 · 0 verified on platform
prediction metrics boltz-2 1.0
ipTM0.493
pTM0.772
avg pLDDT74.9
ranking score0.698
STRUCTURE · PEP-05449 × OPRM1
ranking0.698
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence46 aa
15101520253035404546
ACNTATCMTHRLAGWL SRSGSMVRSNLLPTKM GFKIFNGPRRNSWF
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 2026-06-05

What if a peptide long catalogued as an opioid-like compound actually works through a completely different system in the body?

If the receptor identity is corrected, researchers studying bone density, energy regulation, or heart function could gain a new lead compound, while pain researchers would stop chasing a dead end. Getting the target right is the first step before any drug work can begin.

The hypothesis
CRSP1 (pep-05449) binds the calcitonin receptor (CALCR) or a CALCR/RAMP complex rather than any classical opioid receptor, and its card annotation as an opioid receptor ligand is a mislabeling.
Why it’s plausible
The sole primary reference (10.1016/j.bbrc.2003.11.114) is titled 'Identification, structural determination, and biological activity of bovine and canine calcitonin receptor-stimulating peptides.' CRSP stands for Calcitonin Receptor-Stimulating Peptide. Classical opioid peptides require a Tyr at the N-terminus; the actual sequence begins with Ala-Cys-Asn (ACN...), which lacks this feature entirely. The opioid-axis literature hits in the card are all low-relevance background noise pulled in by the neuropeptide tag, not by the sequence or paper context. CRSP family members in the literature act on CALCR or CALCR/RAMP1-3 heterodimers (analogous to CGRP, amylin, adrenomedullin receptors).
Why it matters
Correct target assignment is prerequisite to any downstream pharmacology. If CRSP1 activates a calcitonin receptor complex, it has implications for bone metabolism, energy homeostasis, and cardiovascular signaling -- a completely different therapeutic space than opioid analgesia.
Plausibility.96
Novelty.28
Impact.93
Basis · grounding1 paper · 2 computed/notes
[1]
paper
Paper title explicitly names calcitonin receptor-stimulating peptides; CRSP acronym is defined therein
doi: 10.1016/j.bbrc.2003.11.114
[2]
sequenceN-terminal tripeptide ACN lacks Tyr, ruling out the canonical opioid pharmacophore (Tyr-Gly-Gly-Phe motif)
[3]
noteTargets field is null, consistent with no confirmed opioid receptor binding
openupdated 2026-06-05

Could a natural peptide quiet pain signals the way calcitonin does, without any risk of opioid dependence?

If this hypothesis holds, CRSP1 might point toward a class of pain drugs that do not carry addiction risk, which would matter enormously for patients needing long-term relief. Drugs targeting the related CGRP pathway already work for migraines; a central-acting cousin could open similar doors for other pain conditions.

The hypothesis
CRSP1 has analgesic activity via calcitonin receptor-dependent mechanisms in the central nervous system, explaining why it was annotated as an opioid-like neuropeptide, but this analgesia is opioid-receptor-independent and mediated by CALCR expressed in the periaqueductal gray and dorsal horn.
Why it’s plausible
Calcitonin produces analgesia through central CALCR activation, independent of opioid receptors. CALCR is expressed in pain-processing regions including the spinal cord dorsal horn and PAG. CRSP1 is a neuropeptide (per its tag) identified in neural-adjacent tissue. If early bioassays showed pain-modulating activity, it may have been misattributed to opioid receptors by pharmacological inference rather than direct receptor evidence. This hypothesis reconciles the 'opioid receptor signaling peptide' label with the calcitonin-receptor provenance.
Why it matters
If CRSP1-type analgesia is opioid-independent, it represents a non-addictive pain modulation pathway. CALCR-targeting analgesics are a growing area given the success of CGRP-pathway drugs in migraine; a novel endogenous CALCR neuropeptide acting centrally could seed new non-opioid analgesic programs.
Plausibility.57
Novelty.52
Impact.70
Basis · grounding1 paper · 1 computed/note
[1]
paper
Biological activity is reported for bovine/canine CRSPs; central nervous system expression context is implied by the neuropeptide classification
doi: 10.1016/j.bbrc.2003.11.114
[2]
noteCard title calls it an opioid receptor signaling peptide despite the parent paper being calcitonin receptor-focused, suggesting an original biological assay showed pain-relevant activity that was contextually attributed to opioid pathways
openupdated 2026-06-05

Could replacing one vulnerable spot in the peptide's chain prevent it from breaking down before it ever reaches a patient?

Peptide drugs often degrade during storage or inside the body before they can do their job. If this substitution works, it could make CRSP1 viable as an actual medicine and would also make it easier to study in the lab, removing a practical barrier that often kills otherwise promising compounds.

The hypothesis
Replacing the methionine at position 8 (Met8, the M in ACNTATCM) with a non-oxidizable residue such as norleucine or leucine will preserve CALCR-binding activity while dramatically improving oxidative stability, because Met8 is immediately adjacent to the Cys1-Cys7 disulfide ring and its sulfoxide form could sterically perturb the ring conformation.
Why it’s plausible
Met oxidation to methionine sulfoxide is a well-known liability in therapeutic peptides, particularly when Met is positioned near a disulfide bridge whose conformation is critical for activity. In CRSP1, Met8 (M in ACNTATCM) sits immediately C-terminal to Cys7. Oxidation of Met8 would introduce a sulfonyl oxygen that creates steric and electrostatic clashes with the ring, likely distorting the critical Cys1-Cys7 loop. Conservative substitution with leucine or norleucine at position 8 has been used successfully in calcitonin analogs to block oxidative degradation.
Why it matters
Met oxidation is a primary degradation pathway for therapeutic peptides under storage and physiological conditions. Solving this for CRSP1 is a prerequisite for drug development and would also stabilize any structural studies of the N-terminal disulfide loop.
Plausibility.68
Novelty.45
Impact.53
Basis · grounding1 paper · 1 computed/note
[1]
sequenceMet at position 8 (ACNTATCM) is directly adjacent to Cys7, placing the oxidation-prone sulfur within bond distance of the disulfide ring
[2]
paper
Structural determination is mentioned in the paper title, suggesting the native disulfide geometry was characterized and its functional importance implied
doi: 10.1016/j.bbrc.2003.11.114
openupdated 2026-06-05

Does a specific shape in the peptide, formed by two linked building blocks at its tip, determine whether it can activate its target receptor?

If this loop is confirmed as the active part of the molecule, drug designers could build smaller, more precise compounds based on it rather than using the whole peptide. That kind of insight tends to speed up development and can improve how selectively a drug acts, reducing unwanted side effects.

The hypothesis
The N-terminal Cys1-Cys7 pair in CRSP1 forms an intramolecular disulfide bridge that creates a constrained loop essential for recognition of the CALCR extracellular domain, analogous to the disulfide-stabilized loops in calcitonin and adrenomedullin.
Why it’s plausible
The sequence ACNTATCM places two cysteines at positions 1 and 7. Calcitonin itself has a 1-7 disulfide ring (Cys1-Cys7) that is critical for receptor binding, and loss of this ring abolishes activity. CRSP1 has the identical cysteine spacing, suggesting it may adopt the same ring topology. This would place the N-terminal loop in the correct geometric register to engage the transmembrane bundle of CALCR.
Why it matters
If the Cys1-Cys7 disulfide is functionally required, it defines the minimal pharmacophore for CRSP1 and explains why linear analogs would be inactive. It also makes the peptide structurally rigid, which would improve selectivity over calcitonin itself if the remaining C-terminal sequence confers receptor-subtype specificity.
Plausibility.57
Novelty.32
Impact.65
Basis · grounding1 paper · 1 computed/note
[1]
sequenceCysteines at positions 1 and 7 (A-C-N-T-A-T-C-M) exactly match the Cys1-Cys7 spacing of human calcitonin
[2]
paper
Structural determination is listed in the title, implying disulfide geometry was characterized for this CRSP family member
doi: 10.1016/j.bbrc.2003.11.114
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.4931243062019348 boltz-2
ranking score 0.6980369687080383 boltz-2
structural qualityopenfold3
metricvaluenote
gpde1.143global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Ala-Cys-Asn-Thr-Ala-Thr-Cys-Met-Thr-His-Arg-Leu-Ala-Gly-Trp-Leu-Ser-Arg-Ser-Gly-Ser-Met-Val-Arg-Ser-Asn-Leu-Leu-Pro-Thr-Lys-Met-Gly-Phe-Lys-Ile-Phe-Asn-Gly-Pro-Arg-Arg-Asn-Ser-Trp-Phe
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). CRSP1 opioid receptor signaling peptide (pep-05449, v1). PeptideModel. https://peptidemodel.com/card/pep-05449
@peptide{pep05449,
  sequence = {ACNTATCMTHRLAGWLSRSGSMVRSNLLPTKMGFKIFNGPRRNSWF},
  target   = {oprm1},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
references 1 papers
discussion no comments
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