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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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Transducer Mechanism: G Protein–Coupled Receptors01:30

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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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GPCR Desensitization01:12

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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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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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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Related Experiment Video

Updated: Aug 19, 2025

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity.

Manbir Sandhu1,2, Aaron Cho3, Ning Ma4

  • 1Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA. msandhu@stjude.org.

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G protein coupled receptors (GPCRs) interact with G proteins through specific contact patterns. Molecular dynamics simulations reveal a spatio-temporal code governing GPCR-G protein selectivity, distinguishing common and specific contacts.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • G protein coupled receptors (GPCRs) exhibit varied coupling to Gα protein subfamilies.
  • The precise mechanisms underlying GPCRs' selective and promiscuous coupling preferences are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing the selective interaction between GPCRs and G proteins.
  • To identify key features of the GPCR:Gα protein interface that dictate coupling specificity.

Main Methods:

  • Utilized Molecular Dynamics (MD) simulations for ten distinct GPCR:G protein complexes.
  • Employed large-scale data analysis of simulation snapshots to derive a spatio-temporal code for interfacial contacts.
  • Validated identified contacts using G protein activation BRET assays.

Main Results:

  • The spatial and temporal dynamics of intermolecular contacts at the GPCR:Gα protein interface are critical for selective coupling.
  • Identified distinct sets of contacts: some common across Gα subfamilies, others specific to particular subfamilies.
  • Promiscuous GPCRs consistently engage common contacts more than G protein-specific contacts.

Conclusions:

  • GPCRs maintain interaction with G proteins via a conserved central interface.
  • Selectivity in GPCR-G protein coupling is conferred by specific contacts located at the periphery of the interface.
  • A spatio-temporal code of interfacial contacts governs GPCR-G protein specificity.