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| Title | Allosteric mechanism in the distinctive coupling of G and G to the parathyroid hormone type 1 receptor. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 122, Issue 13, Page e2426178122, Year 2025 |
| Publish date | Mar 26, 2025 |
 Authors | Xuan Zhang / Ji Young Lee / Jonathan Pacheco / Ieva Sutkeviciute / Anju Krishnan Anitha / Heng Liu / Stephanie Singh / Carlos Ventura / Sofya Savransky / Ashok Khatri / Cheng Zhang / Ivet Bahar / Jean-Pierre Vilardaga /  |
| PubMed 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 ...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, 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 or G. 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 or G 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. |
 External links | Proc Natl Acad Sci U S A / PubMed:40138341 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.49 Å |
| Structure data | EMDB-44229, PDB-9b5y: |
| Source |
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 Keywords | SIGNALING PROTEIN / GPCR / PTH1R / Membrane protein |
Spodoptera frugiperda (fall armyworm)
homo sapiens (human)
mus musculus (house mouse)