Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1.
Acta Pharmacol Sin
; 44(6): 1227-1237, 2023 Jun.
Article
in En
| MEDLINE
| ID: mdl-36482086
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Osteoporosis
/
Parathyroid Hormone-Related Protein
Limits:
Humans
Language:
En
Year:
2023
Type:
Article