Parathyroid hormone fragment that blocks its own receptor (PTH 13: 34)
A lab-made piece of parathyroid hormone, the calcium-regulating hormone, that latches onto its receptor without switching it on, blocking the hormone's normal effect; used only as a lab research tool.
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.
Named peptide fragment — synthesized for research; ClinicalTrials.gov trials registered for parent compound or class
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Endogenous peptide fragment — receptor binding/activity established in published literature; CT.gov evidence
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What this is
PTH (13–34) is a 22-amino-acid fragment of parathyroid hormone — the hormone the parathyroid glands release to keep blood calcium in range. It is the back half of the active 1–34 form: the part that grips the receptor, with the front piece (residues 1–12) that switches the receptor on cut away. Because of that, PTH (13–34) can attach to the PTH1R receptor without triggering a normal hormonal response, and it has been used in laboratory research as a tool to study how PTH and its receptor interact. Its stored sequence is KHLNSMERVEWLRKKLQDVHNF.
History
The two-domain "address–message" view of parathyroid hormone — with the N-terminal residues providing receptor activation and the more C-terminal residues providing the principal binding affinity — has organized PTH structure-activity work for decades and is the basis for splitting the 1–34 sequence into 1–14 / 13–34 style fragments for mechanism studies. The Gardella and colleagues IUPHAR review (Pharmacological Reviews, 2015) summarizes this lineage of work on the parathyroid hormone receptors. The same logic underlies the design of the clinical agonist teriparatide (PTH 1–34), which keeps both halves intact.
What it does
Full-length PTH and the clinically used 1–34 fragment both activate PTH1R, a Class B G-protein-coupled receptor that controls calcium and phosphate handling in bone and kidney (Lee and colleagues, Current Opinion in Nephrology and Hypertension, 2009). PTH (13–34) keeps the receptor-binding half but loses the residues that drive activation, so in cell-based assays it occupies PTH1R without firing the canonical Gαs–cAMP cascade the way intact PTH does. That is the basis for the platform subtitle describing it as a competitive PTH1R fragment — a research tool rather than a therapeutic agonist.
Mechanism
PTH1R is a Class B GPCR with a two-site binding mode: an extracellular N-terminal domain that captures the C-terminal portion of the ligand, and a juxtamembrane region (the seven-helix bundle plus extracellular loops) that the N-terminal residues of the ligand engage to trigger activation. Dean and colleagues (Molecular Endocrinology, 2006) dissected this experimentally using a modified PTH(1–15) radioligand that bound essentially only to the juxtamembrane portion of PTHR, while 125I-PTH(1–34) bound both the N-terminal extracellular domain and the juxtamembrane region — direct evidence that the two halves of PTH 1–34 engage different parts of the receptor. PTH (13–34) is the complementary half: it carries the residues that dock into the extracellular domain but lacks the 1–12 segment that engages the juxtamembrane region to drive Gαs coupling.
Cryo-EM work by Zhao and colleagues (Science, 2019) resolved the active human PTH1R bound to a modified parathyroid hormone and stimulatory G protein, visualizing how the ligand sits across the two binding sites and how activation proceeds. Reviews by Sutkeviciute and colleagues (Trends in Endocrinology & Metabolism, 2019) and Kim and colleagues (Experimental & Molecular Medicine, 2025) place PTH1R within the broader Class B GPCR family and discuss the allosteric coupling and ligand-recognition principles that PTH-fragment studies, including 13–34, have helped establish.
Evidence
- Human: No human clinical trials of PTH (13–34) itself were located in the dossier; the fragment is used in research, while the clinical PTH analogs at PTH1R are the full 1–34 forms teriparatide and abaloparatide (Sato and colleagues, JBMR Plus, 2021).
- Animal / cellular: Radioligand binding studies in cell systems expressing PTHR have used PTH-fragment analogs to map the two-site binding mode of the receptor (Dean and colleagues, 2006). Structural studies on active PTH1R provide the molecular framework these binding studies are interpreted against (Zhao and colleagues, Science, 2019).
- In vitro / structural: Reviews of PTH1R signaling, allostery, and structure (Sutkeviciute and colleagues, 2019; Gardella and colleagues, 2015; Kim and colleagues, 2025) summarize how N-terminal-truncated PTH fragments behave at the receptor.
Known effects
- Receptor binding without canonical activation — Based on the two-site PTH1R binding model, PTH fragments lacking the 1–12 activation residues are expected to engage the receptor's extracellular domain but not drive Gαs signaling the way intact PTH 1–34 does (Dean and colleagues, 2006; Gardella and colleagues, 2015).
- Research-tool use at PTH1R — Used in mechanism studies of how ligand halves contribute to PTH1R engagement (Dean and colleagues, 2006).
Regulatory status
PTH (13–34) is a research fragment, not an approved drug. The approved PTH-pathway agents acting at PTH1R are the full 1–34 forms — teriparatide (recombinant human PTH 1–34) and abaloparatide (a PTHrP-based analog) — both used in osteoporosis (Sato and colleagues, JBMR Plus, 2021). No regulatory approvals, scheduling entries, or WADA listings specific to PTH (13–34) were identified in the dossier.
Related peptides
- Teriparatide (PTH 1–34) — the clinically used full PTH 1–34 fragment; keeps both the activation half (1–12) and the binding half (13–34) and so acts as a PTH1R agonist (Sato and colleagues, 2021).
- Abaloparatide — a PTHrP-derived analog also acting at PTH1R, used for osteoporosis (Sato and colleagues, 2021).
- Long-acting PTH (LA-PTH) — a modified PTH/PTHrP hybrid used in mechanistic comparisons of PTH1R ligands (Sato and colleagues, 2021).
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 peptide work by locking the PTH1R receptor into a specific inactive shape, rather than just sitting in the way of the natural hormone?
If true, it could point toward smarter drugs for hypercalcemia or excessive bone loss that dial the receptor down without fully silencing it, potentially with fewer side effects than complete blockade. Patients with conditions like hyperparathyroidism could benefit from this more nuanced approach.
Could blocking PTH1R with this peptide reduce the damage that cancer cells do when they invade bones?
Bone metastases cause severe pain and fractures in breast and prostate cancer patients, and current treatments slow but rarely stop the damage. A peptide that blocks a key receptor in bone cells could offer a new tool to help keep those metastases in check, potentially used alongside existing bone-protective drugs.
Could attaching a small polymer handle to the free end of PTH(13-34) keep it active in the body long enough to be a practical medicine?
If this works, it could open a new class of treatment for dangerously high calcium levels in cancer patients or people with overactive parathyroid glands, conditions that currently have very limited drug options. A weekly injection rather than continuous infusion would be far more practical for patients.
Does PTH(13-34) block only the PTH1 receptor and not the closely related PTH2 receptor?
If this peptide truly ignores PTH2R, researchers could use it to study bone and kidney calcium problems with much less noise from other receptor pathways. That cleaner picture could accelerate the development of targeted treatments for osteoporosis or kidney-related calcium imbalances.
Is most of the receptor-binding power of PTH(13-34) concentrated in just a small cluster of its amino acids?
If only a tiny part of the peptide is doing the real binding work, chemists could build a much smaller, simpler molecule that mimics the same effect. Smaller molecules are generally easier to manufacture, more stable, and potentially easier to take as a medicine rather than an injection.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.72678142786026 | boltz-2 |
| ranking score | 0.5942230820655823 | 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{pep10781,
sequence = {KHLNSMERVEWLRKKLQDVHNF},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}