Bone-signaling research tool (Tyr36-PTHrP 1-36)
A lab-only synthetic piece of a natural bone-regulating protein, modified to carry a radioactive tag so scientists can track how bone cells receive bone-building signals. Research use 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
(Tyr36)-PTHrP(1-36) is a research-grade synthetic version of the first 36 amino acids of parathyroid hormone-related protein (PTHrP), with the natural C-terminal residue replaced by tyrosine. PTHrP itself is a protein your body makes; its N-terminal fragment looks and acts much like parathyroid hormone (PTH) because both bind the same receptor (PTH1R) on bone and kidney cells (Gardella 2015). The added tyrosine at position 36 carries an aromatic ring that can be tagged with radioactive iodine, so this analog is used in laboratories as a radioligand and tool compound for studying how PTH-family ligands engage their receptor — not as a therapeutic.
History
PTHrP was identified in the late 1980s as the protein responsible for humoral hypercalcemia of malignancy, and was soon recognized as a normal regulator of calcium homeostasis, bone formation, and many developmental processes through the shared PTH/PTHrP receptor (Gardella 2015; Lee 2009). The therapeutic interest in PTH and PTHrP N-terminal fragments grew through the 1990s as it became clear that intermittent receptor activation could build bone rather than break it down — a path that culminated in teriparatide (recombinant human PTH 1-34), whose development history Marcus (2011) recounts as a personal reminiscence of the field. (Tyr36)-PTHrP(1-36) belongs to a family of tyrosine-extended peptide tools that came out of this same era of receptor pharmacology, designed to give researchers a tractable handle on the PTH1R signaling system.
What it does
When (Tyr36)-PTHrP(1-36) binds PTH1R, it triggers the same receptor as native PTH and PTHrP: a class B G protein–coupled receptor expressed on bone-forming osteoblasts and on kidney tubule cells. Activation drives cAMP production through Gαs and also engages calcium signaling, and these pathways together regulate calcium handling, phosphate excretion, and the balance between bone formation and resorption (Gardella 2015; Lee 2009). In cell-culture work on kidney podocytes, PTHrP(1-36) caused cAMP to accumulate and altered intracellular calcium, confirming functional PTH/PTHrP receptor signaling outside the classic bone and kidney-tubule contexts (Endlich 2001).
Mechanism
PTH1R is a class B (secretin-family) GPCR. Cryo-EM of the active human PTH1R in complex with a long-acting PTH analog and stimulatory G protein has resolved how the N-terminal residues of the ligand insert into the receptor's transmembrane bundle to stabilize the active conformation that couples to Gαs (Zhao 2019). N-terminal 1-34 and 1-36 fragments of PTH and PTHrP are sufficient for receptor activation; the C-terminal extension to residue 36 (and the appended Tyr in this analog) lies outside the core agonist pharmacophore and serves primarily as a labeling handle rather than a determinant of intrinsic activity. Different N-terminal PTH/PTHrP ligands — teriparatide (hPTH 1-34), abaloparatide (a PTHrP-based analog), and long-acting PTH — engage the receptor with comparable initial cAMP signaling but differ in how long the active receptor state persists and how the ligand-receptor complex traffics inside the cell, which helps explain their differing clinical effects on bone versus mineral metabolism (Sato 2021).
The stored 36-residue sequence shown here (AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEY) ends in tyrosine; that terminal Y is the (Tyr36) substitution itself and is what allows the peptide to be radioiodinated for binding assays.
Evidence
- Human: No human trials of this specific (Tyr36)-substituted analog. Clinical evidence for PTH1R agonism as a bone-anabolic strategy comes from other family members (teriparatide, abaloparatide); the Tyr36 analog functions as a research tool, not a drug candidate (Gardella 2015; Sato 2021).
- Animal / cell: Used in published in vitro pharmacology of PTHrP signaling — for example, PTHrP(1-36) elicits cAMP accumulation and calcium responses in cultured podocytes, demonstrating functional PTH/PTHrP receptor coupling in those cells (Endlich 2001).
- Structural: The cryo-EM structure of active human PTH1R bound to an N-terminal PTH analog and Gs provides the structural framework for interpreting how 1-34 / 1-36 fragments of this family activate the receptor (Zhao 2019).
Regulatory status
This is a research-only peptide; it is not approved or marketed as a therapeutic in any jurisdiction. Approved PTH1R agonists used clinically for osteoporosis (teriparatide, abaloparatide) and for hypoparathyroidism (long-acting PTH) are separate molecules with their own regulatory dossiers (Sato 2021).
Related peptides
Closely related PTH-family ligands that act through the same PTH1R receptor — these are useful contrast points for understanding what (Tyr36)-PTHrP(1-36) was built to study:
- Teriparatide (recombinant human PTH 1-34) — the prototypical PTH1R bone-anabolic agent (Marcus 2011; Sato 2021).
- Abaloparatide — a PTHrP-based analog optimized for osteoanabolic selectivity (Sato 2021).
- Long-acting PTH (LA-PTH) — engineered for prolonged receptor activation, used as a structural and pharmacological reference ligand (Zhao 2019; Sato 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.
Could swapping the iodine-tagged tyrosine for a fluorine-tagged version create a more stable, longer-lasting tracer for imaging bone receptors in patients?
If it works, doctors could image how many bone receptors a patient has, which would help predict who will respond to drugs like teriparatide and monitor treatment in real time, something not currently possible with available clinical tools.
Is the central part of this peptide disordered and flexible until it docks onto the bone receptor, and does the receptor itself force it to fold?
If the peptide folds only on contact with the receptor, locking it into a pre-folded shape with chemical staples could make it bind much more tightly, potentially leading to more potent and longer-lasting drugs for osteoporosis with lower doses needed.
Does this PTHrP fragment trigger a newly identified signaling route in deep bone cells that is different from what current bone-building drugs activate?
If it does, this could explain why some patients respond better to PTHrP-based drugs than PTH-based ones, and could point the way to a next-generation osteoporosis drug that builds stronger bone with fewer side effects by targeting the right cells more precisely.
Does the added tyrosine at position 36 cause this peptide to bind its receptor in a way that holds on longer than the natural version?
If true, this would explain why structurally similar analogs can have very different effects on bone density, and could guide the design of longer-acting drugs for osteoporosis that work with a single dose rather than daily injections.
Does swapping in a tyrosine at the end make this peptide hit only the bone receptor and not the related receptor found in the brain and other organs?
If true, researchers using this peptide would get cleaner, less ambiguous results in bone experiments, and the finding could guide the design of drugs that target bone and kidney without unwanted side effects in the brain or pancreas.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8838252425193787 | boltz-2 |
| ranking score | 0.6417489647865295 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.612 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10506,
sequence = {AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEY},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}