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Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1


Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.

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Fig. 1: The overall cryo-EM structures of Gs-coupled PTH1R bound to PTH and PTHrP.
Fig. 2: Structure comparisons of PTH1R-Gs complexes by different ligands.
Fig. 3: Molecular recognition of PTH1–34 and PTHrP1–36 by PTH1R.
Fig. 4: G protein coupling of multi-agonist-bound PTH1R.
Fig. 5: Structures of the active PTH1R in G protein-bound state and comparison with structure of the active PTH1R in the absence of G protein.

Data availability

Cryo-EM maps have been deposited in the Electron Microscopy Data Bank under accession codes: EMD-34585 (PTH-bound PTH1R-Gs complex), EMD-34587 (PTHrP-bound PTH1R-Gs complex) and EMD-34598 (dimer of PTH-bound PTH1R-Gs complex). The atomic coordinates have been deposited in the Protein Data Bank under accession codes: 8HA0 (PTH-bound PTH1R-Gs complex), 8HAF (PTHrP-bound PTH1R-Gs complex) and 8HAO (dimer of PTH-bound PTH1R-Gs complex).


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The cryo-EM data were collected by Wen Hu and Kai Wu at Advanced Center for Electron Microscopy at Shanghai Institute of Materia Medica, Chinese Academy of Sciences. We are grateful to them for collecting the cryo-EM data. This work was supported by National Natural Science Foundation of China (32071203 to LHZ; 82073904 to MWW and 81973373 to DHY), the National Key R&D Program of China (2019YFA0904200), the Young Innovator Association of CAS (2018325 to LHZ) and SA-SIBS Scholarship Program to LHZ and DHY; Ministry of Science and Technology (China) grants (2018YFA0507002 to HEX and 2018YFA0507000 to MWW), the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to HEX; 18ZR1447800 to LHZ and 21JC1401600 to DHY), the CAS Strategic Priority Research Program (XDB08020303 to HEX).

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Authors and Affiliations



LHZ designed the expression constructs, purified the complexes, prepared the final samples for negative stain and data collection toward the structures, participated in model building and performed structure and function data analysis, prepared figures and wrote the manuscript; LHZ prepared the cryo-EM grids and QNY collected cryo-EM images and performed map calculations, built and refined the structure models; YWX participated in model refinement; XHH conducted MD simulations; ATD, CWC, CZ and YZ performed signaling experiments under the supervision of DHY and MWW; LHZ and HEX conceived the project, wrote the manuscript.

Corresponding authors

Correspondence to Li-hua Zhao, De-hua Yang or H. Eric Xu.

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The authors declare no competing interests.

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Zhao, Lh., Yuan, Qn., Dai, At. et al. Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1. Acta Pharmacol Sin (2022).

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  • G protein- coupled receptors
  • parathyroid hormone
  • PTH-related peptide
  • PTH receptor-1
  • cryo-electron microscopy structure
  • osteoporosis


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