# Mechanisms of ligand binding and activation at the PTHR1

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $409,092

## Abstract

Abstract The parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor
(PTHR1) plays vital roles in bone development and in maintaining calcium and
phosphate homeostasis. The PTHR1 mediates these roles by binding two distinct
polypeptide hormone ligands - PTHrP and PTH. The PTHR1 is of high medical
importance as it is associated with diseases such as osteoporosis, hypoparathyroidism
and Jansen's metaphyseal chondrodysplasia. This makes the PTHR1 an important
target for therapeutic interventions. Developing effective drugs for the PTHR1 is
challenging, however, especially by rational design approaches. The few drugs currently
available for the PTHR1 are not ideal. For osteoporosis, the two available drugs:
recombinant PTH(1-34), forteo, and a synthetic PTHrP(1-34) analog, abaloparatide,
improve bone parameters but utility is limited by factors such as the need for daily
injection, as the peptides would be destroyed by gut proteases if taken orally, the
potential for adverse effects, such as excess bone resorption and hypercalcemia, and a
waning of anabolic efficacy over time. A better understanding of the molecular
mechanisms by which ligands bind to the PTHR1 and activate signaling is therefore
needed to facilitate the design of more effective PTHR1-based therapies, particularly
ones that are orally active. The studies proposed here aim to reveal such new aspects of
PTHR1 mechanisms, and to thus define how peptides as well as small-molecules bind to
this G protein-coupled receptor and induce selective signaling responses in target cells
that ultimately lead to improvements in human health.
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## Key facts

- **NIH application ID:** 10434872
- **Project number:** 5P01DK011794-54
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** THOMAS J GARDELLA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,092
- **Award type:** 5
- **Project period:** 1997-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434872

## Citation

> US National Institutes of Health, RePORTER application 10434872, Mechanisms of ligand binding and activation at the PTHR1 (5P01DK011794-54). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434872. Licensed CC0.

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