Structure and dynamics of the active human parathyroid hormone receptor-1

Science. 2019 Apr 12;364(6436):148-153. doi: 10.1126/science.aav7942.


The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cryoelectron Microscopy
  • Humans
  • Parathyroid Hormone / chemistry*
  • Parathyroid Hormone / pharmacology
  • Parathyroid Hormone / physiology
  • Protein Binding
  • Protein Domains
  • Receptor, Parathyroid Hormone, Type 1 / agonists*
  • Receptor, Parathyroid Hormone, Type 1 / chemistry*
  • Receptor, Parathyroid Hormone, Type 1 / ultrastructure


  • PTH1R protein, human
  • Parathyroid Hormone
  • Receptor, Parathyroid Hormone, Type 1