Authors
Xudong Wang, Wenkai Sun, Nathaniel Hays, Pangche Wang, Cheng Zhang, Yongbo Zhang, Libin Ye
Published in
bioRxiv : the preprint server for biology. Jul 25, 2026. Epub Jul 25, 2026.
Abstract
Despite decades of research into the signaling efficacy of G protein-coupled receptors (GPCRs), including the resolution of numerous receptor structures in complex with nucleotide-free G proteins 1,2 , mini-G proteins 3,4 , and G protein carboxyl-terminal peptides 5-7 , our understanding of the underlying mechanisms remains elusive, because a fluidic, dynamic view of the conformational transitions during GPCR activation is still missing. Benefiting from its supersensitization to microenvironmental changes, recent advances in 19 F-quantitative NMR ( 19 F-qNMR) 8 enable the dissection and quantification of the conformational energy landscape and dynamics of receptors and their signaling partners, offering new perspectives for deciphering the signaling machinery through a novel lens. Herein, we first established a 3-state model of Gα s conformational landscape and then quantitatively investigated the conformational transitions and dynamics of Gα s proteins in response to different ligand-bound receptors. Our research demonstrated that Gα s substates are not only differentially populated in a ligand-dependent manner but also undergo distinct conformational-cycling kinetics across sub-states in response to different ligand bindings. These discoveries enable us to propose a novel GPCR model that integrates quantitative G protein conformational dynamics at the atomic level to explain GPCR pharmacological efficacy, emphasizing that unique equilibrium and transitions of G protein conformational states in response to ligands are critical determinants of signaling specificity.
PMID:
42538989
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.
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