Stress-hormone fragment (Pro-opiomelanocortin [115-135])
A small piece of the body's stress-hormone precursor protein, found in mouse pituitary tissue; it switches on the receptor that tells the adrenal gland to release cortisol. Used only as a lab research tool.
- Class
- Endogenous peptide fragment (POMC-derived)
- Status
- No approved therapeutic status identified
- Best-supported effect
- None established; peptide was detected and quantified in mouse pituitary tissue by mass spectrometry
- Main caveat
- No bioactivity, pharmacological, or therapeutic evidence is attached to this card
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
POMC [115-135] is a 21-amino acid fragment (RPVKVYPNVAENESAEAFPLE) taken from the middle of pro-opiomelanocortin, the large precursor protein that gives rise to ACTH, the endorphins, and the melanocyte-stimulating hormones. This specific stretch corresponds to residues 115-135 of the mature POMC protein after removal of the signal peptide — a position that falls within the ACTH domain of the precursor — and was identified in mouse pituitary tissue by quantitative peptidomics (Che and colleagues 2005; Pan and colleagues 2006). As a sub-fragment of ACTH that carries part of the adrenal-stimulating sequence, it has been studied in the context of melanocortin 2 receptor (MC2R) binding specificity.
History
Pro-opiomelanocortin was recognized in the late 1970s as a single precursor encoding both ACTH and the endorphins. Over the following decades, mass-spectrometry-based peptidomics revealed that the POMC precursor is processed far more extensively than the canonical cleavage products would suggest, yielding a range of intermediate and sub-fragments detectable in pituitary and hypothalamic tissue. Che and colleagues (2005), working with mouse pituitary using stable isotope-labeled quantitative peptidomics, catalogued numerous POMC-derived peptides including fragments within the ACTH region, and Pan and colleagues (2006) extended this approach to PC2 knockout mouse hypothalamus to map the contribution of individual prohormone convertases to POMC fragment generation. The fragment spanning positions 115-135 of mature POMC was identified in the context of these mouse pituitary peptidomics studies.
What it does
Within POMC, the region covered by this fragment lies inside the ACTH sequence, which normally acts on the adrenal cortex to drive cortisol (in humans) or corticosterone (in rodents) synthesis. ACTH exerts this effect by binding the melanocortin 2 receptor (MC2R), a class A G protein-coupled receptor expressed predominantly in the zona fasciculata of the adrenal cortex, where it activates adenylyl cyclase, raises intracellular cAMP, and activates protein kinase A (PKA), ultimately stimulating steroidogenic gene expression and cholesterol import into mitochondria (Harno and colleagues 2018). The POMC [115-135] fragment contains a portion of the sequence between the two pharmacophore regions of ACTH that are known to be required for MC2R activation — the core HFRW motif and the ACTH-specific KKRRP motif — and has been investigated as a probe of MC2R binding specificity (Cai and colleagues 2016).
Mechanism
MC2R is uniquely selective for ACTH among the five melanocortin receptor subtypes; it does not bind α-MSH or other MSH peptides (Cai and colleagues 2016). Two structural pharmacophores within ACTH are required for receptor activation: the MXHFRW consensus sequence shared with all melanocortins, and a KKRRP C-terminal motif specific to ACTH (the second pharmacophore). Structural studies show that the intervening segment must adopt the correct secondary structure to orient these two motifs properly within the receptor-binding pocket. Because POMC [115-135] is a sub-fragment of ACTH located between these pharmacophore elements, its binding to MC2R is distinct from that of intact ACTH: it lacks the full C-terminal ACTH sequence and the complete KKRRP motif, making it a tool for dissecting which portions of ACTH sequence confer MC2R selectivity. MC2R is only functional at the cell surface in complex with its accessory protein MRAP, which is required for receptor trafficking; inactivating mutations in either MC2R or MRAP cause familial glucocorticoid deficiency in humans.
Evidence
- Human: No clinical studies of the POMC [115-135] fragment as an isolated compound have been published.
- Animal: Detected as a processing product in mouse pituitary tissue by stable-isotope-label peptidomics (Che and colleagues 2005; Pan and colleagues 2006). No registered trials on ClinicalTrials.gov for this peptide.
- In vitro: Investigated in the context of MC2R binding specificity studies as a tool peptide for understanding the ACTH pharmacophore (Cai and colleagues 2016).
Known effects
- POMC precursor context — Within the intact POMC precursor this sequence contributes to adrenal-stimulating ACTH activity; as an isolated fragment, MC2R binding capacity has not been fully characterized independently of the full ACTH sequence — Mechanistic only
- MC2R probe — Used as a research tool to investigate MC2R binding specificity and the structural requirements of the ACTH–MC2R interaction — Mechanistic only
Safety signals
No safety data exist for POMC [115-135] as an isolated peptide. The fragment derives from an endogenous human protein; as a sub-fragment of ACTH it does not contain the complete sequence needed for full MC2R activation as confirmed by structural pharmacology studies (Cai and colleagues 2016). No adverse event data have been reported.
Regulatory status
- US: Not approved. Research compound only. No IND or clinical-stage development identified.
- EU: Not approved. Research compound only.
- WADA: POMC-derived peptides with potential adrenocortical or melanocortin-stimulating activity are generally of interest to anti-doping authorities; this fragment is not individually listed but falls under the broader class of ACTH-related peptides (S2 class — peptide hormones, growth factors, and related substances).
Related peptides
This fragment is a sub-sequence of the full ACTH molecule and derives from the same POMC precursor as α-MSH, β-endorphin, and the other melanocortins. For the biology of the POMC precursor system as a whole, see the Harno and colleagues (2018) review in Physiological Reviews.
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 this fragment of the stress-hormone precursor occupy the cortisol-triggering receptor without actually switching it on, reducing cortisol production?
If this fragment naturally limits cortisol, it could explain why some people have a blunted stress response and suggests a new target for disorders of the HPA axis, including Cushing syndrome or chronic stress conditions where excess cortisol causes metabolic damage.
Do the slightly different lengths of these fragments, produced in different tissues, determine how much cortisol the adrenal gland makes?
If confirmed, this would reveal a previously invisible layer of control over the stress response, explaining individual differences in cortisol reactivity. It could also help researchers design more precise treatments for cortisol disorders that work at the level of hormone processing rather than receptor blockade.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.6937518119812012 | boltz-2 |
| ranking score | 0.7728755474090576 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10638,
sequence = {RPVKVYPNVAENESAEAFPLE},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}