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Cited by 256Receptor Mechanisms and SignalingProtein Structure and DynamicsNeuropeptides and Animal Physiology

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

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Zhao, Li-Hua, Ma, Shanshan, Sutkeviciute, Ieva, Shen, Dan-Dan, Zhou, X. Edward, de Waal, Parker W., Li, Chen-Yao, Kang, Yanyong +16 more·2019·Science
DOI 10.1126/science.aav7942PMC PMC6929210
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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.

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Authors
Zhao, L.-H., Ma, S., Sutkeviciute, I., Shen, D.-D., Zhou, X. E., de Waal, P. W., Li, C.-Y., Kang, Y., Clark, L. J., Jean-Alphonse, F. G., White, A. D., Yang, D., Dai, A., Cai, X., Chen, J., Li, C., Jiang, Y., Watanabe, T., Gardella, T. J., Melcher, K., Wang, M.-W., Vilardaga, J.-P., Xu, H. E., & Zhang, Y.
Affiliations
  • The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Chinese Academy of Sciences (CN)
  • Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • Van Andel Institute (US)
  • Center for Cancer and Cell Biology, Innovation and Integration Program, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • University of Pittsburgh (US)
  • Fudan University (CN)
  • Harvard University (US)
  • Sir Run Run Shaw Hospital (CN)
Corresponding author
  • Ma, Shanshan
  • Wang, Ming-Wei
  • Vilardaga, Jean-Pierre
  • Xu, H. Eric
  • Zhang, Yan
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2019-04-12
Volume
364
Issue
6436
Pages
148-153
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aav7942
PMC
PMC6929210
OpenAlex
W2939681516
Cited by
256
References
59
Citations by year
2026: 27 · 2025: 33 · 2024: 32 · 2023: 31 · 2022: 46 · 2021: 35 · 2020: 41 · 2019: 11
FWCI
11.00
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • National Institutes of Health (R01-DK102495, R01-DK111427, and R01-DK116780, R01 GM129436)
  • Foundation for the National Institutes of Health (GM127710)
  • Van Andel Research Institute
  • Natural Science Foundation of Shanghai (18ZR1447800)
  • the National Natural Science Foundation of China (31770796, 31300245)
  • the Jay and Betty Van Andel Foundation
  • the Fudan-SIMM Joint Research Fund (FU-SIMM-20174003)
  • SA-SIBS Scholarship Program
  • the Youth Innovation Promotion Association (2018325)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
parathyroid hormone type 1 receptor, PTH1R, class B G protein-coupled receptors, receptor activation, G protein coupling, transmembrane domain, transmembrane helix 6, receptor conformational dynamics, calcium homeostasis, osteoporosis, hypoparathyroidism
MeSH terms
Protein Domains, Humans, Parathyroid Hormone, Protein Binding, Cryoelectron Microscopy, Amino Acid Motifs, Receptor, Parathyroid Hormone, Type 1

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