8GGU
Locally refined cryoEM structure of receptor from beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (transition intermediate #13 of 20)
Summary for 8GGU
| Entry DOI | 10.2210/pdb8ggu/pdb |
| Related | 8GG7 |
| EMDB information | 29997 40021 |
| Descriptor | Beta-2 adrenergic receptor, (5R,6R)-6-(methylamino)-5,6,7,8-tetrahydronaphthalene-1,2,5-triol (2 entities in total) |
| Functional Keywords | gpcr, adrenergic, receptor, g protein, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 51976.48 |
| Authors | Papasergi-Scott, M.M.,Skiniotis, G. (deposition date: 2023-03-08, release date: 2024-03-06, Last modification date: 2024-10-30) |
| Primary citation | Papasergi-Scott, M.M.,Perez-Hernandez, G.,Batebi, H.,Gao, Y.,Eskici, G.,Seven, A.B.,Panova, O.,Hilger, D.,Casiraghi, M.,He, F.,Maul, L.,Gmeiner, P.,Kobilka, B.K.,Hildebrand, P.W.,Skiniotis, G. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature, 629:1182-1191, 2024 Cited by PubMed Abstract: G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit. 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 protein in complex with the β-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 Gα switch regions and the α5 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 α-helical domain against the nucleotide-bound Ras-homology domain correlates with α5 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. PubMed: 38480881DOI: 10.1038/s41586-024-07153-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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