期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101279118
关键词
parathyroid hormone receptor 2; cryo-electron microscopy; G protein-coupled receptor; ligand recognition; syndromic short stature
资金
- National Natural Science Foundation of China [81872915, 82073904, 32071203, 81773792, 81973373, 21704064]
- National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program [2018ZX09735-001, 2018ZX09711002-002-005, 2018ZX09711002-002-003]
- National Key Basic Research Program of China [2018YFA0507000]
- Ministry of Science and Technology of China [2018YFA0507002]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Strategic Priority Research Program of Chinese Academy of Sciences [XDB37030103]
- Novo Nordisk-CAS Research Fund [NNCAS-2017-1-CC]
- Shanghai Science and Technology Development Fund [18ZR1447800]
- Young Innovator Association of Chinese Academy of Science [2018325]
- SA-SIBS Scholarship Program
- Youth Innovation Promotion Association of Chinese Academy of Science [2018319]
The study presents the structure of PTH2R bound to its endogenous ligand TIP39 and a heterotrimeric Gs protein, revealing the unique conformation of TIP39 and its mechanism of action on the receptor. It also identifies the basis of ligand specificity relative to TIP39, PTH, and PTH-related peptide, as well as the essential role of the N terminus in PTH2R activation. Additionally, a disease-associated mutation G258D significantly reduced cAMP accumulation induced by TIP39.
The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 angstrom. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
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