# Structural Mechanisms of parathyroid hormone receptor signaling through Gs

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $39,181

## Abstract

Project Abstract
The parathyroid hormone (PTH) type 1 receptor (PTHR) is a key regulator of bone turnover and calcium
homeostasis. PTHR is a G protein-coupled receptor (GPCR) that activates multiple G proteins including
stimulatory Gs, which subsequently activates adenylate cyclases and induces the production of cAMP.
Previous research has suggested that PTHR signaling through Gs is the major mediator of bone anabolism.
Therefore, understanding PTHR-Gs signaling is critical for designing novel drugs to treat bone and mineral-ion
diseases, such as osteoporosis and hypocalcemia.
Two FDA-approved therapeutics for osteoporosis, PTH(1-34) (teriparatide or PTH) and modified PTHrP(1–34)
(abaloparatide or ABL), trigger distinct modes of Gs/cAMP signaling. Both ligands stimulate transient cAMP
production at the plasma membrane. In addition, PTH stimulates prolonged cAMP production in endosomes.
Synthetic long-acting PTH (LA-PTH) promotes endosomal Gs signaling more than does PTH and increases
blood calcium levels in mice and primates. Therefore, LA-PTH is a promising therapeutic for hypocalcemia.
While the cellular effects of PTH, LA-PTH, and ABL have been previously studied, the molecular mechanisms
of biased signaling through each of these three ligands are not known. In the proposed research, we will
investigate the molecular details of PTHR-Gs signaling through two aims. In Aim 1, we will determine atomic
structures of ligand-bound PTHR-Gs complexes via cryo-electron microscopy. These structures will reveal
PTH-, LA-PTH-, and ABL-specific states of PTHR-Gs. In Aim 2, we will identify structural determinants of
ligand-selective PTHR signaling. We will use hydrogen-deuterium exchange (HDX) and chemical crosslinking
(CX) coupled to mass spectrometry (MS) to identify PTHR-Gs complex interfaces in the presence of PTH, LA-
PTH, and ABL. Furthermore, HDXMS will reveal the structural dynamics of PTHR-Gs interactions. The data
from HDXMS and CXMS will be used to design PTHR mutants, whose signaling will be tested in live cells.
Structural and functional data gathered from both aims will give insight into the distinct PTHR-Gs
conformations necessary for transient and prolonged cAMP production. These data will be used in future work
to design novel therapies for osteoporosis and other bone diseases. As such, the proposed research supports
the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

## Key facts

- **NIH application ID:** 9899083
- **Project number:** 5F31AR074843-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Lisa Jean Clark
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,181
- **Award type:** 5
- **Project period:** 2019-03-01 → 2020-12-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899083

## Citation

> US National Institutes of Health, RePORTER application 9899083, Structural Mechanisms of parathyroid hormone receptor signaling through Gs (5F31AR074843-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899083. Licensed CC0.

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