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Related Concept Videos

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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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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Related Experiment Video

Updated: Mar 1, 2026

Capture Compound Mass Spectrometry - A Powerful Tool to Identify Novel c-di-GMP Effector Proteins
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Targeting G Protein-Coupled Receptors by Capture Compound Mass Spectrometry: A Case Study with Sertindole.

Christian Blex1,2, Simon Michaelis1, Anna K Schrey1,3

  • 1caprotec bioanalytics GmbH, Magnusstrasse 11, 12489, Berlin, Germany.

Chembiochem : a European Journal of Chemical Biology
|May 31, 2017
PubMed
Summary

Researchers developed a new method to identify drug targets, specifically G-protein-coupled receptors (GPCRs), in living cells. This capture compound mass spectrometry (CCMS) approach enables precise drug-protein interaction analysis for improved drug discovery.

Keywords:
capture compoundschemoproteomicsmass spectrometrymolecular modelingstructure-activity relationships

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Area of Science:

  • Biochemistry
  • Chemical Biology
  • Pharmacology

Background:

  • Accurate profiling of small-molecule interactions with endogenous proteins is crucial for drug discovery.
  • G-protein-coupled receptors (GPCRs) are a significant class of drug targets but are challenging to study using traditional affinity pulldown methods.
  • Existing chemoproteomic techniques often fall short in comprehensively characterizing drug-protein interactions, particularly for membrane proteins like GPCRs.

Purpose of the Study:

  • To develop and validate a novel capture compound (CC)-based strategy for targeting and identifying GPCRs directly from living cells.
  • To assess the efficacy of CCs designed with sertindole for targeting the dopamine D2 receptor (DRD2).
  • To establish a robust workflow for chemoproteomic profiling of GPCRs using capture compound mass spectrometry (CCMS).

Main Methods:

  • Synthesis of CCs incorporating sertindole in various orientations for DRD2 targeting.
  • Evaluation of CC activity using radioligand displacement and cell-based assays.
  • Application of CCMS for the identification of captured DRD2 in living HEK293 cells.
  • Molecular modeling to rationalize structure-activity relationships.

Main Results:

  • The structure-activity relationship of sertindole for DRD2 binding was successfully mirrored in the activity of the synthesized CCs.
  • The most potent CC exhibited activity comparable to unmodified sertindole.
  • Unambiguous identification of captured DRD2 was achieved using mass spectrometry with less than 100 fmol of receptor in living cells.
  • The CCMS workflow demonstrated high sensitivity and specificity for GPCR identification.

Conclusions:

  • The developed CC-based strategy enables direct targeting and identification of GPCRs in living cells, overcoming limitations of previous methods.
  • This CCMS workflow provides a powerful new tool for unbiased chemoproteomic profiling of drug-GPCR interactions.
  • This advancement significantly enhances the capabilities for comprehensive drug-protein interaction characterization in drug discovery.