25NX

A complex of PTH1R/Gs bound to a PTHrP analogue with three beta-amino acids

Summary for 25NX

• Entry DOI: 10.2210/pdb25nx/pdb
• EMDB information: 80238
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, 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, ... (6 entities in total)
• Functional Keywords: gpcr, g protein, agonist, parathyroid, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 180192.32

Authors

Cary, B.P.,Wootten, D.,Sexton, P.M.,Gellman, S.H.,Wook, T.K.,Shin, J.,Gerrard, E.J. (deposition date: 2026-04-10, release date: 2026-06-03)

Primary citation

Kim, T.W.,Gerrard, E.J.,Shin, J.,Gardella, T.J.,Wootten, D.,Sexton, P.M.,Cary, B.P.,Gellman, S.H.
Altered Intracellular Trafficking as a Mechanism for Prolonged Duration of G Protein-Coupled Receptor Activation.
J.Am.Chem.Soc., 2026

PubMed Abstract: G protein-coupled receptors (GPCRs) mediate information transfer to cells from the surrounding environment. In most cases, signaling is initiated or amplified when the receptor binds to an agonist, an event that alters the conformational profile of the receptor. Signal transduction results from interaction between the agonist-receptor complex and cytosolic partners such as G proteins, GPCR kinases (GRKs), and β-arrestins. Changes in agonist structure can lead to "signal bias", i.e., changes in the relative strength of signaling involving different partners. Some GPCRs, including those activated by long peptide hormones, continue to signal after internalization. In these cases, changes in agonist structure can lead to changes in the relative extent of signaling from different sites, e.g., cell surface vs endosomes ("location bias"). Many GPCRs are targets of approved drugs or drug candidates, and tuning signal bias and/or location bias is widely considered to be important for optimizing therapeutic profiles. Here we report another mechanism of modulating outcome via agonist modification: alteration of intracellular trafficking. The synthetic peptide agonist designated SPT, which contains five β-amino acid residues, was previously shown to activate the parathyroid hormone receptor-1 (PTH1R) and cause prolonged signaling in mice by an unknown mechanism. The SPT-PTH1R complex continues to stimulate cAMP production after internalization. We now find that the SPT-PTH1R complex impairs the sorting of early endosomes into recycling endosomes relative to the receptor complexed to the drug teriparatide. These findings suggest that altering intracellular GPCR trafficking patterns represents an unappreciated strategy for achieving prolonged action .

PubMed: 42159093
DOI: 10.1021/jacs.6c02192

Experimental method

ELECTRON MICROSCOPY (2.86 Å)