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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.
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G-protein Coupled Receptors01:21

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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

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

Marina Casiraghi1, Haoqing Wang1, Patrick C Brennan2

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Science Advances
|March 19, 2025
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This study reveals how G protein-coupled receptors (GPCRs) achieve specific signaling by altering their structure to bind different G proteins. Developing a biased agonist provides new insights into GPCR-G protein interactions.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) show varied selectivity for G protein isoforms, crucial for cellular signaling.
  • The mechanism underlying GPCR-G protein coupling specificity remains largely unknown.
  • The β2-adrenergic receptor preferentially couples to Gαs over Gαi, influencing adenylyl cyclase activity.

Purpose of the Study:

  • To investigate the structural basis of G protein coupling specificity in GPCRs.
  • To understand how distinct GPCR conformations dictate Gαs versus Gαi engagement.
  • To explore the potential for designing biased ligands targeting specific signaling pathways.

Main Methods:

  • Development of a Gαi-biased agonist (LM189) for the β2-adrenergic receptor.
  • Structural analysis of GPCR-G protein interactions.
  • Biophysical assays to characterize receptor-G protein binding and signaling.

Main Results:

  • Distinct conformational states at the intracellular loop 2 (ICL2) and transmembrane helix 6 (TM6) are critical for selective G protein coupling.
  • The developed Gαi-biased agonist (LM189) demonstrated differential engagement with Gαs and Gαi.
  • Structural and biophysical data elucidated the molecular determinants of G protein subtype specificity.

Conclusions:

  • Specific receptor conformations at ICL2 and TM6 are key to distinguishing between Gαs and Gαi binding.
  • Understanding these conformational differences enables the rational design of ligands with pathway-selective signaling.
  • This research advances the field of GPCR pharmacology and drug discovery by enabling precise control over signaling outcomes.