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Publication Abstract from PubMed

Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Galphabetagamma structures, these snapshots primarily capture the fully activated complex. Consequently, the functions of intermediate GPCR-G protein complexes remain elusive. Guided by a conformational landscape visualized via (19)F quantitative NMR and molecular dynamics (MD) simulations, we determined the structure of an intermediate GPCR-mini-Galpha(s)betagamma complex at 2.6 A using cryo-EM, by blocking its transition to the fully activated complex. Furthermore, we present direct evidence that the complex at this intermediate state initiates a rate-limited nucleotide exchange before transitioning to the fully activated complex. In this state, BODIPY-GDP/GTP based nucleotide exchange assays further indicated the alpha-helical domain of the Galpha is partially open, allowing it to grasp a nucleotide at a non-canonical binding site, distinct from the canonical nucleotide-binding site. These advances bridge a significant gap in our understanding of the complexity of GPCR signaling.

Structure and function of a near fully-activated intermediate GPCR-Galphabetagamma complex.,Bi M, Wang X, Wang J, Xu J, Sun W, Adediwura VA, Miao Y, Cheng Y, Ye L Nat Commun. 2025 Jan 28;16(1):1100. doi: 10.1038/s41467-025-56434-4. PMID:39875358^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.