Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1
© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:44 |
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| Enthalten in: |
Acta pharmacologica Sinica - 44(2023), 6 vom: 08. Juni, Seite 1227-1237 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhao, Li-Hua [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2023 Date Revised 25.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41401-022-01032-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349944156 |
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| 245 | 1 | 0 | |a Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1 |
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| 520 | |a © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a G protein- coupled receptors | |
| 650 | 4 | |a PTH receptor-1 | |
| 650 | 4 | |a PTH-related peptide | |
| 650 | 4 | |a cryo-electron microscopy structure | |
| 650 | 4 | |a osteoporosis | |
| 650 | 4 | |a parathyroid hormone | |
| 650 | 7 | |a Parathyroid Hormone-Related Protein |2 NLM | |
| 650 | 7 | |a Parathyroid Hormone |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 700 | 1 | |a Yuan, Qing-Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, An-Tao |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xin-Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chuan-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, You-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ming-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, De-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, H Eric |e verfasserin |4 aut | |
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