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TitleMolecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1.
Journal, issue, pagesActa Pharmacol Sin, Vol. 44, Issue 6, Page 1227-1237, Year 2023
Publish dateDec 8, 2022
AuthorsLi-Hua Zhao / Qing-Ning Yuan / An-Tao Dai / Xin-Heng He / Chuan-Wei Chen / Chao Zhang / You-Wei Xu / Yan Zhou / Ming-Wei Wang / De-Hua Yang / H Eric Xu /
PubMed AbstractParathyroid 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 ...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.
External linksActa Pharmacol Sin / PubMed:36482086 / PubMed Central
MethodsEM (single particle)
Resolution2.62 - 3.76 Å
Structure data

34585

8ha0

EMDB-34585, PDB-8ha0:
Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1
Method: EM (single particle) / Resolution: 2.62 Å

34587

8haf

EMDB-34587, PDB-8haf:
PTHrP-PTH1R-Gs complex
Method: EM (single particle) / Resolution: 3.25 Å

34598

8hao

EMDB-34598, PDB-8hao:
Human parathyroid hormone receptor-1 dimer
Method: EM (single particle) / Resolution: 3.76 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

Source
  • homo sapiens (human)
  • bos taurus (cattle)
  • rattus norvegicus (Norway rat)
  • synthetic construct (others)
KeywordsLIPID BINDING PROTEIN/HORMONE/IMMUNE SYSTEM / PTH1R / GPCR / LIPID BINDING PROTEIN-HORMONE-IMMUNE SYSTEM complex

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