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Journal Articles Science Year : 2019

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

Li-Hua Zhao
  • Function : relator_co_first_author
Ieva Sutkeviciute
Dan-Dan Shen
  • Function : relator_co_first_author
X. Edward Zhou
  • Function : Author
Parker de Waal
  • Function : Author
Chen-Yao Li
  • Function : Author
Yanyong Kang
  • Function : Author
Lisa Clark
  • Function : Author
Alex White
  • Function : Author
Dehua Yang
  • Function : Author
Antao Dai
  • Function : Author
Xiaoqing Cai
  • Function : Author
Jian Chen
Cong Li
  • Function : Author
Yi Jiang
  • Function : Author
Tomoyuki Watanabe
  • Function : Author
Thomas Gardella
  • Function : Author
Karsten Melcher
  • Function : Author
Ming-Wei Wang
  • Function : Author
Jean-Pierre Vilardaga
H. Eric Xu
  • Function : Author
Yan Zhang

Abstract

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.

Dates and versions

hal-03117165 , version 1 (20-01-2021)

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Li-Hua Zhao, Shanshan Ma, Ieva Sutkeviciute, Dan-Dan Shen, X. Edward Zhou, et al.. Structure and dynamics of the active human parathyroid hormone receptor-1. Science, 2019, 364 (6436), pp.148-153. ⟨10.1126/science.aav7942⟩. ⟨hal-03117165⟩
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