Related Experiment Video
Updated: Jun 29, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Conformational changes involved in G-protein-coupled-receptor activation
Jürgen Wess1, Sung-Jun Han, Soo-Kyung Kim
1Molecular Signaling Section and Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jwess@helix.nih.gov
Trends in Pharmacological Sciences
|October 8, 2008
Summary
Structural changes in G-protein-coupled receptors (GPCRs) during activation are revealed using disulfide cross-linking. These insights into M3 muscarinic acetylcholine receptor activation offer potential therapeutic strategies.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- G-protein-coupled receptors (GPCRs) undergo conformational changes from resting to active states upon ligand binding, a process not fully understood.
- Understanding these molecular mechanisms is crucial for developing targeted therapeutics.
Purpose of the Study:
- To elucidate the structural rearrangements involved in GPCR activation.
- To gain insights into the conformational changes of the M3 muscarinic acetylcholine receptor, a class I GPCR.
Main Methods:
- Utilizing disulfide cross-linking strategies with cysteine-substituted mutant GPCRs.
- Employing the M3 muscarinic acetylcholine receptor as a model system for activation studies.
Main Results:
- Identified key conformational changes during GPCR activation.
- Predicted structural alterations involve transmembrane helices III, VI, VII, and helix 8.
- Findings from the M3 receptor suggest general relevance for other GPCRs due to structural homology.
Conclusions:
- Disulfide cross-linking provides valuable structural insights into GPCR activation mechanisms.
- The identified conformational changes are likely conserved across various GPCRs.
- A deeper understanding of GPCR activation can inform novel therapeutic interventions.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
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 affinity and are together...
01:21G-protein Coupled Receptors
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.
01:21G-protein Coupled Receptors
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.
01:15G Protein-coupled Receptors
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...
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...
01:15G Protein-coupled Receptors
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...
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...
01:30Transducer Mechanism: G Protein–Coupled Receptors
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, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...