8HAF

PTHrP-PTH1R-Gs complex

Summary for 8HAF

• Entry DOI: 10.2210/pdb8haf/pdb
• EMDB information: 34585 34587 34598
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (8 entities in total)
• Functional Keywords: pth1r, gpcr, lipid binding protein-hormone-immune system complex, lipid binding protein/hormone/immune system
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 6
• Total formula weight: 172705.61

Authors

Zhao, L.,Xu, H.E.,Yuan, Q. (deposition date: 2022-10-26, release date: 2022-12-21, Last modification date: 2025-05-14)

Primary citation

Zhao, L.H.,Yuan, Q.N.,Dai, A.T.,He, X.H.,Chen, C.W.,Zhang, C.,Xu, Y.W.,Zhou, Y.,Wang, M.W.,Yang, D.H.,Xu, H.E.
Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1.
Acta Pharmacol.Sin., 44:1227-1237, 2023

PubMed 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.

PubMed: 36482086
DOI: 10.1038/s41401-022-01032-z

Experimental method

ELECTRON MICROSCOPY (3.25 Å)