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Related Concept Videos

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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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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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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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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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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Updated: Feb 26, 2026

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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Allostery between Distant Structural Regions Dictates Selectivity in GPCR:G Protein Coupling.

Elizaveta Mukhaleva1,2, Edgardo J Sánchez Rivas3, Sergio Branciamore1,2

  • 1Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Monrovia, California 91016, United States.

Biochemistry
|February 25, 2026
PubMed
Summary
This summary is machine-generated.

Understanding G-protein coupled receptor-G (GPCR-G) protein coupling selectivity is key. Cooperative interactions within the Gα protein core, identified using machine learning and simulations, can engineer Gα proteins for specific signaling pathways.

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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • G-protein coupled receptor-G (GPCR-G) protein coupling selectivity mechanisms are not fully understood.
  • Extensive structural and functional studies have yet to resolve these molecular underpinnings.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing GPCR-G protein coupling selectivity.
  • To identify key residue communities within the Gα protein core influencing this selectivity.

Main Methods:

  • Interpretable machine learning Bayesian Network model.
  • Molecular Dynamics simulations.
  • Experimental validation including subtype-swapping mutations.

Main Results:

  • Identified distinct cooperative hotspot residues in the Gα protein core (N-terminus, h4s6 loop, H5 helix) across subtypes.
  • Revealed allosteric dependencies between the Gα core and H5 helix for selective interactions.
  • Demonstrated that Gαq-like mutations in Gαs core alter receptor coupling to Gαq.

Conclusions:

  • Cooperative interactions within the Gα core are critical for GPCR-G protein coupling selectivity.
  • These interactions can be engineered to create Gα proteins with customized signaling preferences.