Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor.

Autor: Batebi H; Universität Leipzig, Medizinische Fakultät, Institut für Medizinische Physik und Biophysik, Leipzig, Germany.; Freie Universität Berlin, Fachbereich Physik, Berlin, Germany., Pérez-Hernández G; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany., Rahman SN; University of Copenhagen, Department of Drug Design and Pharmacology, Copenhagen, Denmark., Lan B; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China., Kamprad A; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Structural Biology of Cellular Signaling, Berlin, Germany., Shi M; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China., Speck D; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Structural Biology of Cellular Signaling, Berlin, Germany., Tiemann JKS; Universität Leipzig, Medizinische Fakultät, Institut für Medizinische Physik und Biophysik, Leipzig, Germany.; Novozymes A/S, Lyngby, Denmark., Guixà-González R; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.; Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain., Reinhardt F; Universität Leipzig, Department of Computer Science, Bioinformatics, Leipzig, Germany., Stadler PF; Universität Leipzig, Department of Computer Science, Bioinformatics, Leipzig, Germany., Papasergi-Scott MM; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Skiniotis G; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Scheerer P; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Structural Biology of Cellular Signaling, Berlin, Germany., Kobilka BK; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Mathiesen JM; University of Copenhagen, Department of Drug Design and Pharmacology, Copenhagen, Denmark., Liu X; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China., Hildebrand PW; Universität Leipzig, Medizinische Fakultät, Institut für Medizinische Physik und Biophysik, Leipzig, Germany. peter.hildebrand@medizin.uni-leipzig.de.; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany. peter.hildebrand@medizin.uni-leipzig.de.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Nov; Vol. 31 (11), pp. 1692-1701. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1038/s41594-024-01334-2
Abstrakt: G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound G s protein (G s ·GDP; hereafter G s GDP ) upon coupling to the β 2 -adrenergic receptor (β 2 AR) in atomic detail. The binding of G s GDP to the β 2 AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the G s occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this β 2 AR-G s GDP intermediate, G s undergoes an in-plane rotation along the receptor axis to approach the β 2 AR-G s empty state. The simulations shed light on how the structural elements at the receptor-G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity.
Competing Interests: Competing interests G.S. is a co-founder of, and consultant for, Deep Apple Therapeutics. B.K.K. is a co-founder of, and consultant for, ConfometRx.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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