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β2-adrenergic receptor in complex with GTP-bound G protein Gs, vitrified 17 seconds after addition of GTP

ABSTRACT:

SUBMITTER: Georgios Skiniotis

PROVIDER: EMPIAR-11858 | 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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Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations.

Project description:G protein-coupled receptors (GPCRs) are transmembrane proteins of high pharmacological relevance. It has been proposed that their activity is linked to structurally distinct, dynamically interconverting functional states and the process of activation relies on an interconnecting network of conformational switches in the transmembrane domain. However, it is yet to be uncovered how ligands with different extents of functional effect exert their actions. According to our recent hypothesis, based on indirect observations and the literature data, the transmission of the external stimulus to the intracellular surface is accompanied by the shift of macroscopic polarization in the transmembrane domain, furnished by concerted movements of highly conserved polar motifs and the rearrangement of polar species. In this follow-up study, we have examined the β2-adrenergic receptor (β2AR) to see if our hypothesis drawn from an extensive study of the μ-opioid receptor (MOP) is fundamental and directly transferable to other class A GPCRs. We have found that there are some general similarities between the two receptors, in agreement with previous studies, and there are some receptor-specific differences that could be associated with different signaling pathways.

| S-EPMC8508748 | biostudies-literature

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.

| S-EPMC3184188 | biostudies-literature

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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Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound ?1-adrenergic receptor.

Project description:A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., Gs and ?-arrestin. Using 13C methyl methionine NMR for the ?1-adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with Gs-mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive ?s-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.

| S-EPMC5702606 | biostudies-literature

Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies

Project description:G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. We report the cryo-EM structures of β1-adrenergic receptor (β1-AR) in complex with Gs (GαsGβ1Gγ2) and a partial agonist or a very weak partial agonist, and compare them to the β1-AR–Gs structure in complex with a full agonist. Analyses reveal similar overall complex architecture, with local conformational differences. Cellular functional studies with mutations of β1-AR residues show effects on the cellular signaling from β1-AR to the cAMP response initiated by the three different ligands, with residue-specific functional differences. Biochemical investigations uncover that the intermediate state complex comprising β1-AR and nucleotide-free Gs is more stable when binding a full agonist than a partial agonist. Molecular dynamics simulations support the local conformational flexibilities and different stabilities among the three complexes. These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins. Su et al. report cryo-EM structures of β1-adrenergic receptor, Gs and ligands of different efficacies. These complexes have similar overall architecture, but with local conformational differences and different stabilities.

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β2-adrenergic receptor regulates ER-mitochondria contacts.

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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Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor.

Project description:Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β1-adrenergic receptor (β1-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by β1-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which β1-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gαs. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the β6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.

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