PTHrP(7-34) blocker: research tool for bone and calcium studies (Hypercalcemia Malignancy Factor fragment)
A lab-only peptide fragment that plugs the receptor tumors use to dangerously raise blood calcium, without switching it on, used to study how bone and calcium are controlled. Research tool only.
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
PTHrP(7-34) amide is a 28-residue research peptide derived from parathyroid hormone-related protein (PTHrP), the same hormone tumors release to drive hypercalcemia of malignancy. It is used in the lab as an antagonist at the PTH1R receptor — the receptor that both parathyroid hormone (PTH) and PTHrP activate to control calcium and bone. The peptide is the C-terminal binding domain of PTHrP with the N-terminal activating residues lopped off, so it occupies the receptor without switching it on. The stored sequence LLHDKGKSIQDLRRRFFLHHLIAEIHTA is the bare backbone; the active research compound carries a C-terminal amide (the "-NH₂" cap), which is not visible in the raw letters.
History
The shared PTH/PTHrP receptor was first isolated in 1992 by expression cloning from rat osteoblast-like cells, establishing that PTH and PTHrP — despite their very different physiological roles — both act through a single common class B GPCR (Abou-Samra 1992). That cloning made it possible to dissect the receptor's pharmacology with truncated ligands. Removing the N-terminal residues (positions 1–6) of PTH or PTHrP converts the full agonist into a competitive antagonist, because the deleted residues are the ones that engage the receptor's transmembrane core and trigger signaling. PTHrP(7-34) amide became one of the standard tool antagonists in that program. The receptor was later formally classified by IUPHAR as the PTH1R, a family B G protein-coupled receptor (Gardella 2015).
What it does
PTHrP(7-34) amide binds the extracellular domain of PTH1R but does not flip the receptor into its active conformation. Because PTH and PTHrP both rely on this same receptor to raise blood calcium, stimulate bone remodeling, and signal through cAMP and intracellular calcium pathways (Abou-Samra 1992), occupying it with a "headless" ligand blocks those effects. In practice this gives researchers a way to test whether a bone or kidney response depends on PTH1R signaling: if PTHrP(7-34) amide abolishes it, the pathway runs through PTH1R.
Mechanism
PTH1R is a class B G protein-coupled receptor that couples to Gαs (driving cAMP production via adenylyl cyclase) and to Gαq (driving inositol trisphosphate and intracellular calcium release) — both signals were demonstrated for the cloned receptor in the original expression-cloning paper (Abou-Samra 1992). Native PTH and PTHrP engage the receptor through a two-domain mechanism: the C-terminal portion of the ligand docks into the receptor's extracellular N-terminal domain, while the N-terminal residues of the ligand insert into the juxtamembrane region containing the transmembrane helices and extracellular loops to trigger activation (Dean 2006). PTHrP(7-34) amide retains the docking C-terminal portion (residues 7–34) but lacks residues 1–6, so it binds the extracellular domain competitively without engaging the juxtamembrane activation site. The C-terminal amide is the standard cap used for synthetic PTH-family fragments to mimic the natural processed C-terminus and protect the C-terminal carboxyl from carboxypeptidases. Skeletal context is laid out in the broader PTH1R signaling literature, where PTH1R activity intersects with CaSR signaling to govern osteoblast and osteoclast biology (Santa Maria 2016), and where PTH1R-dependent bone responses can be modulated by intracellular adapters such as Kindlin-2 (Fu 2020) — these are the kinds of downstream effects an antagonist like PTHrP(7-34) amide is used to dissect.
Evidence
- Human: No clinical use. A related N-terminally truncated PTH antagonist, BIM-44002, was tested in hypercalcemic hyperparathyroid patients and lowered serum calcium and PTH levels (Rosen 1997); PTHrP(7-34) amide itself remains a research tool rather than a drug candidate.
- Animal: Used in rodent skeletal and calcium-handling studies as a PTH1R blocker; the underlying PTH1R biology those studies probe has been characterized in mouse models including conditional PTH1R-pathway disruption (Fu 2020).
- In vitro: Binds the cloned PTH/PTHrP receptor in osteoblast-derived cells (Abou-Samra 1992); used in radioligand binding studies on PTH1R to distinguish ligand interactions with the extracellular versus juxtamembrane portions of the receptor (Dean 2006).
Known effects
- PTH1R antagonism — Standard research-grade competitive antagonist at PTH1R; blocks PTH- and PTHrP-induced cAMP and calcium signaling in PTH1R-expressing cells.
- Discriminates anabolic vs. catabolic PTH1R signaling — Used as a pharmacological probe to assign skeletal or renal responses to PTH1R rather than to other calcium-regulating pathways (Gardella 2015).
- No agonist activity — Lacks the N-terminal residues (1–6) required to activate the receptor's transmembrane core (Dean 2006).
Regulatory status
- Research use only. PTHrP(7-34) amide is not an approved drug in any jurisdiction and is not in clinical development. It is used as a laboratory tool compound.
Related peptides
- Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) — the two endogenous agonists at PTH1R that this fragment is designed to block (Abou-Samra 1992; Gardella 2015).
- Other N-terminally truncated PTH/PTHrP antagonists in the same research family include BIM-44002, which was advanced into human hypercalcemia studies (Rosen 1997).
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.
Would chemically bridging two nearby amino acids in PTHrP(7-34) make it stable enough in the bloodstream to actually reduce dangerously high calcium?
High blood calcium from cancer is a life-threatening emergency. PTHrP(7-34) failed partly because it degraded too fast. A stapled, longer-lasting version could be the calcium-lowering drug that cancer patients currently lack.
Could blocking the PTH receptor in joint cartilage cells stop the process that erodes the joint surface in osteoarthritis?
Osteoarthritis affects hundreds of millions of people and has no treatment that stops its progression, only pain management. If PTHrP(7-34) can halt cartilage self-destruction by blocking a single receptor, it could become the first true disease-modifying drug for this condition.
Does PTHrP(7-34) cause the PTH receptor to disappear from the cell surface through a back-door signaling pathway, undermining its own effectiveness?
If this blocker unintentionally removes the receptor it is supposed to antagonize, it explains why it failed in clinical trials for high calcium in cancer patients, and points toward redesigned analogues that block without causing receptor loss.
Can we use the near-perfect receptor-fit prediction for PTHrP(7-34) to map exactly which part of the receptor it locks without activating?
Understanding precisely how this peptide blocks the PTH receptor without triggering it could guide the design of improved calcium-regulating drugs for people with dangerously high calcium from cancer or hyperparathyroidism.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9266836643218994 | boltz-2 |
| ranking score | 0.6855012774467468 | 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{pep10617,
sequence = {LLHDKGKSIQDLRRRFFLHHLIAEIHTA},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {computed}
}