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β2-adrenergic receptor in complex with nucleotide-free G protein Gs

ABSTRACT:

SUBMITTER: Georgios Skiniotis

PROVIDER: EMPIAR-11855 | biostudies-other |

REPOSITORIES: biostudies-other

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Time-resolved cryo-EM of G-protein activation by a GPCR.

Papasergi-Scott Makaía M MM Pérez-Hernández Guillermo G Batebi Hossein H Gao Yang Y Eskici Gözde G Seven Alpay B AB Panova Ouliana O Hilger Daniel D Casiraghi Marina M He Feng F Maul Luis L Gmeiner Peter P Kobilka Brian K BK Hildebrand Peter W PW Skiniotis Georgios G

Nature 20240313 8014

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit1. 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 Gs protein in complex with the β2-adrenergic receptor at short sequential time points after GTP additio ...[more]

PMID: 38480881

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Crystal structure of the ?2 adrenergic receptor-Gs protein complex.

Project description:G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The ?(2) adrenergic receptor (?(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric ?(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the ?(2)AR and Gs involve the amino- and carboxy-terminal ?-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the ?(2)AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an ?-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the ?-helical domain of G?s relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.

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β2-adrenergic receptor in complex with GTP-bound G protein Gs, vitrified 5 seconds post-GTP addition

Project description: Not available

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Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations.

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Project description: Not available

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β2-adrenergic receptor in complex with GTP-bound G protein Gs, vitrified 10 seconds after addition of GTP

Project description: Not available

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Transmitting the Signal: Structure of the β1-Adrenergic Receptor-Gs Protein Complex.

Project description:In this issue of Molecular Cell, Su et al. (2020) report a cryo-EM structure of the β1-adrenergic receptor (β1AR) in complex with a heterotrimeric Gs protein, which offers novel insights into receptor activation and provides a structural framework to better understand the transducer-coupling mechanism for adrenergic receptors.

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Computational study on the different ligands induced conformation change of ?2 adrenergic receptor-Gs protein complex.

Project description:?2 adrenergic receptor (?2AR) regulated many key physiological processes by activation of a heterotrimeric GTP binding protein (Gs protein). This process could be modulated by different types of ligands. But the details about this modulation process were still not depicted. Here, we performed molecular dynamics (MD) simulations on the structures of ?2AR-Gs protein in complex with different types of ligands. The simulation results demonstrated that the agonist BI-167107 could form hydrogen bonds with Ser203(5.42), Ser207(5.46) and Asn293(6.55) more than the inverse agonist ICI 118,551. The different binding modes of ligands further affected the conformation of ?2AR. The energy landscape profiled the energy contour map of the stable and dissociated conformation of G?s and G?? when different types of ligands bound to ?2AR. It also showed the minimum energy pathway about the conformational change of G?s and G?? along the reaction coordinates. By using interactive essential dynamics analysis, we found that G?s and G?? domain of Gs protein had the tendency to separate when the inverse agonist ICI 118,551 bound to ?2AR. The ?5-helix had a relatively quick movement with respect to transmembrane segments of ?2AR when the inverse agonist ICI 118,551 bound to ?2AR. Besides, the analysis of the centroid distance of G?s and G?? showed that the G?s was separated from G?? during the MD simulations. Our results not only could provide details about the different types of ligands that induced conformational change of ?2AR and Gs protein, but also supplied more information for different efficacies of drug design of ?2AR.

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Project description:Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.

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Conformational changes in the G protein Gs induced by the ?2 adrenergic receptor.

Project description:G protein-coupled receptors represent the largest family of membrane receptors that instigate signalling through nucleotide exchange on heterotrimeric G proteins. Nucleotide exchange, or more precisely, GDP dissociation from the G protein ?-subunit, is the key step towards G protein activation and initiation of downstream signalling cascades. Despite a wealth of biochemical and biophysical studies on inactive and active conformations of several heterotrimeric G proteins, the molecular underpinnings of G protein activation remain elusive. To characterize this mechanism, we applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs (the stimulatory G protein for adenylyl cyclase) on formation of a complex with agonist-bound human ?(2) adrenergic receptor (?(2)AR). Here we report structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the ?(2)AR-Gs complex. Together with X-ray crystallographic and electron microscopic data of the ?(2)AR-Gs complex (from refs 2, 3), we provide a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the ?-subunit of Gs and consequently alters the 'P-loop' that binds the ?-phosphate in GDP. As with the Ras family of small-molecular-weight G proteins, P-loop stabilization and ?-phosphate coordination are key determinants of GDP (and GTP) binding affinity.

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