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

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

Author information

1
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
2
University of Chinese Academy of Sciences, Beijing 100049, China.
3
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
4
Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, China.
5
Center for Cancer and Cell Biology, Innovation and Integration Program, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
6
Graduate Program in Molecular Biophysics and Structural Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
7
Graduate Program in Molecular Pharmacology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
8
School of Pharmacy, Fudan University, Shanghai 201203, China.
9
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
10
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. eric.xu@vai.org mwwang@simm.ac.cn jpv@pitt.edu zhang_yan@zju.edu.cn.
11
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. eric.xu@vai.org mwwang@simm.ac.cn jpv@pitt.edu zhang_yan@zju.edu.cn.
12
Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, China. eric.xu@vai.org mwwang@simm.ac.cn jpv@pitt.edu zhang_yan@zju.edu.cn.
#
Contributed equally

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.

PMID:
30975883
DOI:
10.1126/science.aav7942
[Indexed for MEDLINE]

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