Related Experiment Video
Updated: Feb 24, 2026
10:13
Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
17.3K
The Gαi-GIV binding interface is a druggable protein-protein interaction
Vincent DiGiacomo1, Alain Ibáñez de Opakua2, Maria P Papakonstantinou1
1Department of Biochemistry, Boston University School of Medicine, Boston, USA.
Scientific Reports
|August 19, 2017
Summary
Researchers identified druggable inhibitors for the Gαi-GIV protein interaction, a key driver of cancer metastasis. This discovery validates Gαi-GIV as a therapeutic target and offers a framework for developing new anti-cancer drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Heterotrimeric G proteins are typically activated by GPCRs, but non-receptor GEFs also exist.
- GIV (Girdin) is the first identified non-receptor GEF with a defined sequence that binds Gαi.
- GIV promotes cancer metastasis, and disrupting Gαi-GIV binding reduces this effect.
Purpose of the Study:
- To investigate if the Gαi-GIV protein-protein interaction (PPI) is a druggable target.
- To validate Gαi-GIV as a potential therapeutic target for cancer treatment.
Main Methods:
- In silico ligand screening of over 1,000 compounds.
- Chemical high-throughput screening (HTS) assay for Gαi-GIV PPI inhibitors.
- NMR spectroscopy and biochemical assays to identify binding sites and specificity.
Main Results:
- Two compounds, ATA and NF023, were identified as hits in both in silico and HTS screens.
- NF023's binding site overlaps the Gαi-GIV interface, confirmed by NMR and biochemical assays.
- NF023 specifically inhibits Gαi-GIV interaction without affecting Gαi-Gβγ binding.
Conclusions:
- The Gαi-GIV PPI is a druggable target.
- Establishes a framework for discovering novel inhibitors of the Gαi-GIV PPI.
- Suggests potential for new therapeutic strategies targeting cancer metastasis.
Related Concept Videos
02:04Protein-protein Interfaces
14.9K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
14.9K
02:04Protein-Protein Interfaces
4.5K
4.5K
01:30Transducer Mechanism: G Protein–Coupled Receptors
5.2K
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,...
5.2K
01:22Activation and Inactivation of G Proteins
11.8K
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...
11.8K
01:15G Protein-coupled Receptors
18.1K
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...
18.1K
01:30Assembly of Signaling Complexes
6.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.7K