ArticleScientific reports2017
The Gαi-GIV binding interface is a druggable protein-protein interaction.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- Inhibitory probes for spatiotemporal analysis of GαNature chemical biology · 2026Article
- Modeling NDD-Associated NLGN2 Depletion Using CRISPR/Cas13 Reveals Exaggerated Process Elongation Mediated by the CCDC88A-G Protein-ELMO Axis.International journal of molecular sciences · 2026Article
- Signaling Through Girdin Underlies Excessive Cell Morphogenesis Resulting from Depletion of Neurodevelopmental Disorder-Related Neurexin-2.International journal of molecular sciences · 2026Article
- GRespiratory research · 2024Review
- Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Systematic identification of structure-specific protein-protein interactions.Molecular systems biology · 2024Article
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Article
- Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targeting Gαi/s Proteins with Peptidyl Nucleotide Exchange Modulators.ACS chemical biology · 2022Article
- Building unconventional G protein-coupled receptors, one block at a time.Trends in pharmacological sciences · 2021Article
- Strategies towards Targeting Gαi/s Proteins: Scanning of Protein-Protein Interaction Sites To Overcome Inaccessibility.ChemMedChem · 2021Review
- Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein.eLife · 2020Article
- A biochemical and genetic discovery pipeline identifies PLCδ4b as a nonreceptor activator of heterotrimeric G-proteins.The Journal of biological chemistry · 2018Article
- Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Gαi. GIV expression promotes metastasis and disruption of its binding to Gαi blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Gαi-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly "druggable" targets requiring case-by-case validation. Here, we set out to investigate whether Gαi-GIV is a druggable PPI. We tested a collection of >1,000 compounds on the Gαi-GIV PPI by in silico ligand screening and separately by a chemical high-throughput screening (HTS) assay. Two hits, ATA and NF023, obtained in both screens were confirmed in secondary HTS and low-throughput assays. The binding site of NF023, identified by NMR spectroscopy and biochemical assays, overlaps with the Gαi-GIV interface. Importantly, NF023 did not disrupt Gαi-Gβγ binding, indicating its specificity toward Gαi-GIV. This work establishes the Gαi-GIV PPI as a druggable target and sets the conceptual and technical framework for the discovery of novel inhibitors of this PPI.
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