Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex

Maxine Bi, Xudong Wang, Jinan Wang, Jun Xu, Wenkai Sun, Victor Ayo Adediwura, Yinglong Miao (), Yifan Cheng () and Libin Ye ()
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Maxine Bi: University of California
Xudong Wang: 4202 E Fowler Ave
Jinan Wang: University of North Carolina at Chapel Hill, 116 Manning Drive
Jun Xu: Stanford University School of Medicine
Wenkai Sun: 4202 E Fowler Ave
Victor Ayo Adediwura: University of North Carolina at Chapel Hill, 116 Manning Drive
Yinglong Miao: University of North Carolina at Chapel Hill, 116 Manning Drive
Yifan Cheng: University of California
Libin Ye: 4202 E Fowler Ave

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ 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 19F quantitative NMR and molecular dynamics (MD) simulations, we determined the structure of an intermediate GPCR-mini-Gαsβγ complex at 2.6 Å 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 α-helical domain of the Gα 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.

Date: 2025
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DOI: 10.1038/s41467-025-56434-4

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