Download MendeleyStructure and function of a near fully-activated intermediate GPCR-G alpha beta gamma complex.
Bi, M., Wang, X., Wang, J., Xu, J., Sun, W., Adediwura, V.A., Miao, Y., Cheng, Y., Ye, L.(2025) Nat Commun 16: 1100-1100
- PubMed: 39875358
- DOI: https://doi.org/10.1038/s41467-025-56434-4
- Primary Citation of Related Structures:
9EE8, 9EE9, 9EEA - PubMed 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 19 F quantitative NMR and molecular dynamics (MD) simulations, we determined the structure of an intermediate GPCR-mini-Gα s βγ 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.
Organizational Affiliation:
Department of Biochemistry and Biophysics, University of California, 600 16th Street, San Francisco, CA, 94143, USA.
