Related Experiment Video
Updated: Mar 30, 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
9.6K
How Can Mutations Thermostabilize G-Protein-Coupled Receptors?
Nagarajan Vaidehi1, Reinhard Grisshammer2, Christopher G Tate3
1Division of Immunology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Trends in Pharmacological Sciences
|November 9, 2015
Summary
Understanding G-protein-coupled receptors (GPCRs) is key for drug design. Molecular dynamics simulations reveal mutations stabilize GPCRs by increasing rigidity and reducing motion, aiding structure-based drug discovery.
Area of Science:
- Biochemistry and structural biology
- Computational biophysics
Background:
- Over 30 G-protein-coupled receptor (GPCR) structures advance cell signaling and drug design.
- GPCR crystallization requires methods like thermostabilization via mutagenesis.
Purpose of the Study:
- To elucidate the energetic factors contributing to GPCR thermostability.
- To understand why specific mutations stabilize GPCRs, which is not always clear from static structures.
Main Methods:
- Employed molecular dynamics (MD) simulations.
- Compared dynamics of thermostabilized GPCRs with wild-type models to identify energetic contributions.
Main Results:
- Receptor stabilization results from increased rigidity and decreased collective motion.
- Reduced residue stress and presence of ordered water molecules also contribute to stability.
- Identified key energetic factors influencing GPCR thermostability.
Conclusions:
- MD simulations are valuable for understanding GPCR stabilization mechanisms.
- Predicting thermostabilizing mutations computationally remains a significant challenge.
Related Concept Videos
01:12GPCR Desensitization
8.7K
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...
8.7K
01:30Transducer Mechanism: G Protein–Coupled Receptors
7.7K
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,...
GPCRs are also called heptahelical,...
7.7K
01:22Activation and Inactivation of G Proteins
12.4K
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...
12.4K
01:21G-protein Coupled Receptors
134.2K
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.
134.2K
01:21G-protein Coupled Receptors
7.0K
7.0K
01:15G Protein-coupled Receptors
19.6K
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...
19.6K