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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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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

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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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GPCRs Regulate Adenylyl Cylase Activity01:09

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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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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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Updated: Dec 23, 2025

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

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Improved GPCR ligands from nanobody tethering.

Ross W Cheloha1, Fabian A Fischer1, Andrew W Woodham1

  • 1Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA.

Nature Communications
|May 1, 2020
PubMed
Summary

Researchers developed novel nanobody-peptide conjugates for targeted G protein-coupled receptor (GPCR) activation. These CLAMP conjugates enhance the potency and specificity of therapeutic peptides, showing improved activity in vitro and in vivo.

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Area of Science:

  • Bioconjugation chemistry
  • Molecular pharmacology
  • Drug delivery systems

Background:

  • Antibody-drug conjugates enable targeted delivery of therapeutics.
  • Nanobodies (VHHs) offer specific antigen recognition.
  • G protein-coupled receptors (GPCRs) are key drug targets.

Purpose of the Study:

  • To develop a novel C-to-C conjugate strategy for enhancing peptide ligand activity.
  • To improve the signaling activity and specificity of parathyroid hormone (PTH) peptide fragments.
  • To create targeted therapeutics for parathyroid hormone receptor-1 (PTHR1).

Main Methods:

  • Fusion of nanobodies (VHHs) recognizing PTHR1 with PTH peptide fragments.
  • Development of the "conjugation of ligands and antibodies for membrane proteins" (CLAMP) approach.
  • In vitro and in vivo testing of conjugate biological activity and specificity.

Main Results:

  • C-to-C nanobody-peptide conjugates demonstrated superior in vitro biological activity compared to parent peptides.
  • A VHH-PTH peptide conjugate showed biological activity in mice, unlike the free peptide.
  • The lead conjugate exhibited enhanced selectivity for PTHR1 over PTH(1-34).

Conclusions:

  • The CLAMP approach yields potent and specific ligands for membrane proteins.
  • Nanobody-peptide conjugates represent a promising strategy for targeted GPCR therapeutics.
  • This method can overcome limitations of poorly active peptide fragments.