Bone-building cancer-calcium peptide: PTHrP (1-34) fragment
A fragment of a protein that some tumors release to raise blood calcium; in controlled doses it stimulates bone growth by activating the same receptor as parathyroid hormone. Experimental, not an approved drug.
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
This is the N-terminal 1–34 fragment of parathyroid hormone-related protein (PTHrP), the factor historically called "humoral hypercalcemia of malignancy factor" — the substance that certain tumors secrete to drive blood calcium upward in cancer patients. PTHrP was purified from a human lung cancer cell line and named for this clinical syndrome, but it later turned out to be a normal developmental and skeletal hormone in its own right (Moseley 1987). The 1–34 fragment retains the receptor-binding activity of the full protein and is built around the same parathyroid hormone 1 receptor (PTH1R) that PTH itself uses (Gardella 2015). The stored sequence is shown here as a 34-residue chain with a C-terminal amide cap, which is how this fragment is typically synthesized for laboratory and pharmacological use; the -NH₂ cap is not visible in the raw single-letter sequence.
History
PTHrP was identified in 1987 when Moseley and colleagues purified an 18 kDa protein from the conditioned medium of the BEN human lung cancer cell line, a tumor type associated with paraneoplastic hypercalcemia (Moseley 1987). N-terminal sequencing of the purified factor showed that 8 of the first 16 residues were identical to human PTH, immediately establishing the molecule as a structural cousin of parathyroid hormone — and explaining why tumors expressing it could mimic primary hyperparathyroidism. That discovery opened a long arc of work on the PTH/PTHrP receptor and on synthetic 1–34 fragments as bone-anabolic drug leads, eventually leading to the development of abaloparatide, a clinical PTHrP(1–34) analog (Brent 2021).
What it does
PTHrP(1–34) binds and activates PTH1R, a class B G-protein-coupled receptor expressed on osteoblasts, kidney tubule cells, and chondrocytes (Gardella 2015). PTH1R is the same receptor used by parathyroid hormone — the two ligands share the same binding site even though their full-length sequences diverge after the N-terminus. Through PTH1R, intermittent exposure to PTH or PTHrP(1–34) stimulates bone formation: in mice, intermittent PTH increases bone volume fraction and bone mineral density, an effect that depends on intact PTH1R signaling in osteoblastic cells (Fu 2020). This is the same biology that underpins the bone-anabolic drug class to which the closely related synthetic analog abaloparatide belongs (Brent 2021).
Mechanism
PTHrP(1–34) and PTH(1–34) bind PTH1R in two interconverting conformations, conventionally labeled R⁰ (a high-affinity, more stable complex) and RG (a G-protein-coupled, transient complex). Hattersley and colleagues (2016) showed that abaloparatide — a synthetic PTHrP(1–34) analog — preferentially selects the RG conformation, producing more transient cAMP signaling than PTH(1–34), and proposed that this kinetic difference underlies abaloparatide's more anabolic, less resorptive, less hypercalcemic profile in animal models. The native PTHrP(1–34) fragment represented by this card sits in the same conformational landscape and engages the same Gαs-cAMP output, but without the rebalanced kinetics introduced by the abaloparatide substitutions. Downstream of PTH1R in bone, intact integrin adaptor signaling is required for the anabolic response: deletion of Kindlin-2 in osteoblastic cells in mice largely neutralizes intermittent PTH's effect on bone volume and BMD by impairing both osteoblast and osteoclast formation (Fu 2020).
Evidence
- Human: No clinical-trial data on PTHrP(1–34) itself as a drug in the references for this card. The clinical evidence base for the closely related synthetic PTHrP(1–34) analog abaloparatide is summarized in a dedicated review (Brent 2021). A separate small clinical study in hypercalcemic hyperparathyroid patients tested a PTH receptor antagonist, BIM-44002, and observed acute effects on serum calcium and PTH levels (Rosen 1997) — relevant as proof-of-concept for PTH1R pharmacology in humans, not as evidence for the agonist 1–34 fragment.
- Animal: Intermittent PTH increases bone volume fraction and bone mineral density in adult mice through PTH1R on osteoblastic cells; this response is largely lost when the integrin adaptor Kindlin-2 is deleted in those cells (Fu 2020). Preclinical work on the synthetic PTHrP(1–34) analog abaloparatide is reviewed by Brent (2021).
- In vitro: PTHrP(1–34) and the abaloparatide analog engage PTH1R in two conformations (R⁰ and RG) with different selectivities, producing different cAMP-signaling kinetics in receptor-expressing cells (Hattersley 2016). The native PTHrP factor was first purified to homogeneity from BEN human lung carcinoma cell culture medium, where it migrated as an 18 kDa band on SDS-PAGE and shared 8 of 16 N-terminal residues with human PTH (Moseley 1987).
Known effects
- Bone-anabolic signaling at PTH1R — established in vitro and in animal models for PTH/PTHrP(1–34) and for the synthetic analog abaloparatide (Hattersley 2016; Fu 2020; Brent 2021).
- Hypercalcemic / PTH-mimetic activity — PTHrP is the founding factor of the humoral hypercalcemia of malignancy syndrome and was originally purified on the strength of its PTH-like bioactivity (Moseley 1987).
- Receptor pharmacology distinct from PTH(1–34) — preferential engagement of the RG conformation of PTH1R relative to the R⁰ state, characterized for the abaloparatide analog (Hattersley 2016).
Regulatory status
The native peptide represented by this card — synthetic PTHrP(1–34) amide — is not itself an approved drug. The clinically developed PTHrP(1–34) analog abaloparatide is reviewed by Brent (2021) and is the relevant entry point for the regulatory and clinical context of this molecular family; structural parathyroid-hormone-receptor pharmacology for the broader class is set out in the IUPHAR receptor review (Gardella 2015). This card does not provide dosing, route-of-use, or treatment guidance.
Related peptides
- Abaloparatide — synthetic PTHrP(1–34) analog with PTH1R-RG-selective signaling characterized in detail (Hattersley 2016; Brent 2021).
- Parathyroid hormone (PTH) and PTH(1–34) / teriparatide — the other endogenous PTH1R ligand and its bone-anabolic 1–34 fragment, sharing the PTH1R binding site with PTHrP(1–34) (Gardella 2015).
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 run of three arginine residues in PTHrP(1-34) help decide whether the peptide favors bone-building signals over receptor-shutdown signals?
If this patch helps balance the two signals, changing one or two amino acids might let PTHrP-based osteoporosis drugs keep working longer before bone stops responding. That could help patients who need safer, longer-lasting treatment.
Can PTHrP(1-34) also act on pancreatic cells that carry the bone receptor, helping them release insulin?
If so, patients on PTHrP-based bone drugs might also get a blood-sugar benefit. Older adults often have both conditions, so one treatment touching both would mean fewer medicines.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8442076444625854 | openfold3-mlx |
| ranking score | 0.9602436423301697 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.839 | global PDE — lower = better |
| disorder | 0.311 | ! high disorder |
| chain pair ipTM (A, B) | 0.844 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 847s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
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
@peptide{pep10502,
sequence = {AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTA},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}