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Related Concept Videos

Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
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G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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G-protein Coupled Receptors01:21

G-protein Coupled Receptors

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding

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Structure and dynamics determine G protein coupling specificity at a class A GPCR.

Marina Casiraghi, Haoqing Wang, Patrick Brennan

    Biorxiv : the Preprint Server for Biology
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    G protein coupled receptors (GPCRs) show varying selectivity for G protein subtypes. New research reveals distinct receptor conformations are key for specific G protein coupling, aiding targeted drug design.

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    G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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    Area of Science:

    • Pharmacology
    • Structural Biology
    • Biochemistry

    Background:

    • G protein coupled receptors (GPCRs) interact with specific G protein isoforms, influencing cellular signaling.
    • The β2-adrenergic receptor typically couples to Gαs but shows weak interaction with Gαi.
    • Understanding the molecular basis of G protein coupling specificity is crucial for drug discovery.

    Purpose of the Study:

    • To investigate the structural mechanisms underlying G protein coupling selectivity in GPCRs.
    • To characterize the interaction of a novel Gαi-biased agonist with the β2-adrenergic receptor.

    Main Methods:

    • Development of a Gαi-biased agonist (LM189).
    • Structural analysis of GPCR-G protein complexes.
    • Biophysical assays to determine binding affinities and functional outcomes.

    Main Results:

    • Distinct conformational states of the β2-adrenergic receptor are required for Gαs and Gαi coupling.
    • The novel agonist LM189 demonstrates Gαi-biased signaling.
    • Structural evidence highlights the roles of ICL2 and TM6 in determining G protein subtype specificity.

    Conclusions:

    • G protein coupling specificity is mediated by distinct GPCR conformations.
    • Targeting specific conformations can lead to biased agonists with improved signaling pathway selectivity.
    • Findings facilitate the design of novel therapeutics targeting GPCRs.