8ge7
CryoEM structure of beta-2-adrenergic receptor in complex with nucleotide-free Gs heterotrimer (#8 of 20)
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedG-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Galpha subunit(1). To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G-protein complex. By monitoring the transitions of the stimulatory G(s) protein in complex with the beta(2)-adrenergic receptor at short sequential time points after GTP addition, we identified the conformational trajectory underlying G-protein activation and functional dissociation from the receptor. Twenty structures generated from sequential overlapping particle subsets along this trajectory, compared to control structures, provide a high-resolution description of the order of main events driving G-protein activation in response to GTP binding. Structural changes propagate from the nucleotide-binding pocket and extend through the GTPase domain, enacting alterations to Galpha switch regions and the alpha5 helix that weaken the G-protein-receptor interface. Molecular dynamics simulations with late structures in the cryo-EM trajectory support that enhanced ordering of GTP on closure of the alpha-helical domain against the nucleotide-bound Ras-homology domain correlates with alpha5 helix destabilization and eventual dissociation of the G protein from the GPCR. These findings also highlight the potential of time-resolved cryo-EM as a tool for mechanistic dissection of GPCR signalling events. Time-resolved cryo-EM of G-protein activation by a GPCR.,Papasergi-Scott MM, Perez-Hernandez G, Batebi H, Gao Y, Eskici G, Seven AB, Panova O, Hilger D, Casiraghi M, He F, Maul L, Gmeiner P, Kobilka BK, Hildebrand PW, Skiniotis G Nature. 2024 May;629(8014):1182-1191. doi: 10.1038/s41586-024-07153-1. Epub 2024 , Mar 13. PMID:38480881[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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