8uns: Difference between revisions
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8uns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uns OCA], [https://pdbe.org/8uns PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uns RCSB], [https://www.ebi.ac.uk/pdbsum/8uns PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uns ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8uns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uns OCA], [https://pdbe.org/8uns PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uns RCSB], [https://www.ebi.ac.uk/pdbsum/8uns PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uns ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | |||
G-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<ref>PMID:38480881</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8uns" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 08:27, 12 June 2024
CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (Class H)CryoEM structure of beta-2-adrenergic receptor in complex with GTP-bound Gs heterotrimer (Class H)
Structural highlights
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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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