Allosteric mechanism in the distinctive coupling of G <sub>q</sub> and G <sub>s</sub> to the parathyroid hormone type 1 receptor

The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G<sub>s</sub>, we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G<sub>s</sub> or G<sub>q</sub>. Single-cell-level experiments further validate the G protein-selective effects of the PTH binding pose by demonstrating the differential, G protein-dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G<sub>s</sub> or G<sub>q</sub> and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-03-26
DOI
https://doi.org/10.1073/pnas.2426178122
Citations
1
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
Field-Weighted Citation Impact
0.81

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article

Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor

Cheng Zhang, Sofya Savransky, Sweta Singh, Carlos Ventura et al.
1 citations
Proceedings of the National Academy of Sciences
Protein Kinase Regulation and GTPase Signaling
0.81
article

Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor

Cheng Zhang, Sofya Savransky, Sweta Singh, Carlos Ventura, Jonathan Pacheco, Ashok Khatri, Jean‐Pierre Vilardaga, İvet Bahar, Ji Young Lee, Ieva Sutkevičiu̅tė, Xuan Zhang, Heng Liu, Anju Krishnan Anitha
article en
1 citations

Abstract

The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G<sub>s</sub>, we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G<sub>s</sub> or G<sub>q</sub>. Single-cell-level experiments further validate the G protein-selective effects of the PTH binding pose by demonstrating the differential, G protein-dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G<sub>s</sub> or G<sub>q</sub> and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.

Proceedings of the National Academy of SciencesVol. 122(13)
United States Department of Veterans Affairs (US), Harvard University (US), University of Pittsburgh (US), Veterans Health Administration (US), Stony Brook School (US), Massachusetts General Hospital (US), Stony Brook University (US)
U.S. Department of Veterans Affairs, University of Wisconsin-Madison, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 30%
Protein Kinase Regulation and GTPase Signaling
0.81
DOIOpen Access PDFOpenAlex
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