{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:08:03Z","timestamp":1785323283046,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,25]]},"group-title":"Biophysics","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:sup>1,2<\/jats:sup>\n                  , mini-G proteins\n                  <jats:sup>3,4<\/jats:sup>\n                  , and G protein carboxyl-terminal peptides\n                  <jats:sup>5\u20137<\/jats:sup>\n                  , 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\n                  <jats:sup>19<\/jats:sup>\n                  F-quantitative NMR (\n                  <jats:sup>19<\/jats:sup>\n                  F-qNMR)\n                  <jats:sup>8<\/jats:sup>\n                  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 G\u03b1\n                  <jats:sub>s<\/jats:sub>\n                  conformational landscape and then quantitatively investigated the conformational transitions and dynamics of G\u03b1\n                  <jats:sub>s<\/jats:sub>\n                  proteins in response to different ligand-bound receptors. Our research demonstrated that G\u03b1\n                  <jats:sub>s<\/jats:sub>\n                  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.\n                <\/jats:p>","DOI":"10.64898\/2026.07.23.740425","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:32:01Z","timestamp":1785130321000},"source":"Crossref","is-referenced-by-count":0,"title":["Ligand-Specified Signaling Efficacy Defined by Unique Transitions in G Protein Conformations"],"prefix":"10.64898","author":[{"given":"Xudong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA 33620;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenkai","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA 33620;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Hays","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA 33620;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pangche","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL, USA 60208;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0818-2972","authenticated-orcid":false,"given":"Libin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA 33620;"},{"name":"H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL, USA 33612"},{"name":"Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA, USA 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