Cortisol-pathway research fragment (ACTH [7-31])
A lab-only fragment of the stress hormone ACTH, used to study how ACTH tells the adrenal gland to make cortisol; not a drug or treatment.
- Class
- Endogenous peptide fragment (ACTH-derived)
- Status
- No approved therapeutic status identified
- Main caveat
- Porcine-derived peptide sequence entry with no attached assay, animal, or human evidence. No functional characterization is present in the source file.
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
ACTH [7-31] is a 25-residue fragment of adrenocorticotropic hormone (ACTH), spanning positions 7 through 31 of the full 39-amino-acid sequence. It is not a drug or therapeutic agent — it is a biochemical research tool used to map which parts of ACTH are required for activity at the melanocortin 2 receptor (MC2R), the adrenal receptor that ACTH normally activates to trigger cortisol release. The sequence stored here is derived from porcine ACTH, which differs from the human sequence at a small number of positions; this is a species variant, not a universal human peptide.
Full-length ACTH is produced in the pituitary gland from a larger precursor protein called proopiomelanocortin (POMC), which is processed into several bioactive fragments in a tissue-specific manner (Harno and colleagues 2018). The [7-31] fragment is one of many fragments studied to define the structure-activity relationship of ACTH at its primary receptor.
History
ACTH was among the first pituitary hormones to be fully sequenced. The complete structure of the porcine POMC mRNA and its encoded protein — from which ACTH and the ACTH [7-31] sequence are derived — was determined from cloned cDNA by Boileau and colleagues in 1983, allowing precise mapping of every peptide fragment the precursor can generate. Interest in ACTH fragments intensified as researchers sought to understand why MC2R, alone among the five melanocortin receptors, responds exclusively to ACTH and not to shorter melanocortin peptides. The [7-31] fragment, covering the central and C-terminal portion of ACTH while lacking the biologically critical N-terminal residues, became a useful probe in dissecting this specificity.
What it does
The first 13 residues of full-length ACTH (positions 1–13) contain the sequence shared with α-melanocyte-stimulating hormone and are sufficient to activate MC1R, MC3R, MC4R, and MC5R. MC2R, by contrast, requires additional determinants in the C-terminal extension of ACTH that the α-MSH core alone cannot provide, making it the most receptor-selective of the melanocortin targets (Fridmanis and colleagues 2017). The [7-31] fragment retains part of this C-terminal region while lacking the intact N-terminus, and it has been used as a structural probe to investigate which regions of ACTH contribute to MC2R engagement and which are dispensable.
MC2R itself is expressed predominantly on adrenocortical cells and is required for normal adrenal gland development and cortisol synthesis. In MC2R-knockout mice, adrenal steroidogenesis fails and gluconeogenesis is impaired in the neonatal period, demonstrating the receptor's essential role in adrenal physiology (Chida and colleagues 2007).
Evidence
- Human: No human studies of the ACTH [7-31] fragment itself have been identified in the literature indexed in this dossier. Clinical evidence for the parent hormone (full-length ACTH and its synthetic 1-24 fragment cosyntropin) is extensive but specific to those forms.
- Animal: MC2R knockout mouse studies have characterized the consequences of absent ACTH signaling at the adrenal level, confirming the receptor's requirement for steroidogenesis and adrenal development (Chida and colleagues 2007).
- In vitro: The [7-31] fragment has been employed in receptor-binding studies examining MC2R specificity; the molecular basis of MC2R's selectivity for ACTH over shorter melanocortin peptides is reviewed in Fridmanis and colleagues (2017).
Mechanism
ACTH drives cortisol synthesis by binding MC2R, a class A G-protein-coupled receptor (GPCR) coupled to Gs, on adrenocortical cells. Receptor activation raises intracellular cyclic AMP, which activates protein kinase A and in turn the steroidogenic acute regulatory protein (StAR), the rate-limiting step in cholesterol transport into the mitochondria and subsequent steroid synthesis (Harno and colleagues 2018). What distinguishes MC2R from the other four melanocortin receptors is its strict ligand requirement: only ACTH, not α-MSH or other shorter melanocortin peptides, activates it efficiently. The molecular determinants of this selectivity — and where in ACTH's sequence they reside — have been the central question motivating fragment studies of which ACTH [7-31] is a part (Fridmanis and colleagues 2017). The broader melanocortin receptor family, including MC5R, and their roles in signaling across health and disease contexts are reviewed in Cai and colleagues (2016) and Xu and colleagues (2020).
Open questions
- Exactly which residues within ACTH [7-31] are necessary or sufficient for MC2R binding, and what structural conformation they adopt in the receptor-bound state, remain active areas of investigation.
- Whether porcine and human ACTH [7-31] differ in receptor binding pharmacology at MC2R has not been systematically characterized in the indexed literature.
- A high-resolution crystal or cryo-EM structure of MC2R in complex with full-length ACTH or any ACTH fragment has not been published as of the indexed sources.
Related peptides
The ACTH [7-31] fragment belongs to the POMC-derived peptide family. The parent hormone and its clinical fragments are closely related:
- Full-length ACTH (1-39) and cosyntropin (1-24) — the biologically active and clinically used forms; cosyntropin (the synthetic 1-24 fragment) is the standard adrenal stimulation agent and retains full MC2R agonist activity that the [7-31] fragment lacks in its N-terminus.
- The melanocortin receptor system more broadly is shared with α-MSH, which activates MC1R, MC3R, MC4R, and MC5R but not MC2R (Fridmanis and colleagues 2017; Cai and colleagues 2016).
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 acidic end of ACTH grab a separate spot on the adrenal receptor that shorter hormone fragments cannot reach?
If true, this would explain a 50-year-old puzzle about why the adrenal gland's receptor only responds to the full hormone. It could help researchers design precise drugs for adrenal insufficiency that avoid side effects from activating other related receptors.
Could the positively charged middle section of ACTH bind sugar-coated proteins on adrenal cells, helping the hormone accumulate where it is needed?
If ACTH uses the cell surface as a staging ground, this could explain why adrenal responses remain robust even when blood hormone levels are very low, and might point to new ways to treat conditions where the adrenal gland responds poorly to ACTH.
Does this partial version of ACTH turn on only part of the adrenal receptor's signaling machinery, potentially causing fewer unwanted effects?
If this fragment drives cortisol production through a cleaner signaling path, it could form the basis of better treatments for adrenal insufficiency with reduced risk of receptor fatigue or unwanted hormonal side effects.
Could this fragment of the stress hormone ACTH also activate the brain's appetite-control receptor, suppressing hunger independently of its adrenal effects?
If so, it would reveal a natural link between the stress hormone system and weight regulation, potentially opening a path toward appetite-suppressing peptide drugs that work through this overlooked route.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7102804780006409 | boltz-2 |
| ranking score | 0.7808865904808044 | 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{pep10543,
sequence = {FRWGKPVGKKRRPVKVYPNGAEDEL},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}