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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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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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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

4.0K
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,...
4.0K
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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G-protein Coupled Receptors01:21

G-protein Coupled Receptors

131.6K
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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Related Experiment Video

Updated: Jan 18, 2026

Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells
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Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells

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Atypical GPCR Activation Resolved by Nanobody Engineering.

Roman R Schlimgen1,2, Shawn E Jenjak1, Alexa De La Sancha1

  • 1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, USA.

Biorxiv : the Preprint Server for Biology
|January 16, 2026
PubMed
Summary
This summary is machine-generated.

Researchers discovered a new way G protein-coupled receptors (GPCRs) activate, focusing on extracellular pocket volume changes instead of traditional conformational shifts. This finding offers novel strategies for targeting difficult-to-treat receptors.

Keywords:
ACKR3ChemokineCryo-EMGPCRNMRNanobodyVHH

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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells

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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are a major drug target class.
  • Most therapeutics target only a small fraction of well-characterized GPCRs.
  • The atypical chemokine receptor ACKR3 presents unique challenges due to its broad ligand recognition and high basal activity.

Purpose of the Study:

  • To elucidate the unconventional activation mechanism of the ACKR3 receptor.
  • To challenge established paradigms of GPCR activation.
  • To identify new strategies for modulating GPCRs, including pharmacologically intractable ones.

Main Methods:

  • Engineered nanobodies
  • Cryo-electron microscopy (cryo-EM)
  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Structure-guided pharmacology

Main Results:

  • ACKR3 activation is controlled by extracellular pocket volume, not conserved microswitch conformational changes.
  • An expanded aromatic cluster in the intracellular transducer binding pocket stabilizes the active receptor state.
  • This reveals an unconventional mechanism distinct from canonical GPCR activation models.

Conclusions:

  • ACKR3 activation mechanism redefines GPCR modulation strategies.
  • Findings provide new avenues for targeting previously intractable GPCRs.
  • This research broadens the understanding of GPCR signaling and drug discovery potential.