ArticleThe Journal of biological chemistry2019
Rational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890.The Journal of biological chemistry · 2025Article
- Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated GMolecular pharmacology · 2024Review
- Stabilization of interdomain closure by a G protein inhibitor.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy.Chemical science · 2024Article
- Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate GαACS pharmacology & translational science · 2023Review
- The Bacterial GJournal of chemical ecology · 2023Article
- Article
- IGF1R Inhibition Enhances the Therapeutic Effects of Gq/11 Inhibition in Metastatic Uveal Melanoma Progression.Molecular cancer therapeutics · 2023Article
- Imaging of GαPharmaceutics · 2022Article
- How Carvedilol activates βNature communications · 2022Article
- Article
- A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action.Journal of cell communication and signaling · 2022Review
- GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation.Nature communications · 2022Article
- Targeting Oncogenic GαCancers · 2021Review
- Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359.Nature communications · 2021Article
- Functional characterization of uveal melanoma oncogenes.Oncogene · 2021Article
- Delineation of molecular determinants for FR900359 inhibition of GThe Journal of biological chemistry · 2020Article
- Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as GαChemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.Nature communications · 2020Article
- Heterotrimeric GThe Journal of biological chemistry · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Transmembrane signals initiated by a range of extracellular stimuli converge on members of the Gq family of heterotrimeric G proteins, which relay these signals in target cells. Gq family G proteins comprise Gq, G11, G14, and G16, which upon activation mediate their cellular effects via inositol lipid-dependent and -independent signaling to control fundamental processes in mammalian physiology. To date, highly specific inhibition of Gq/11/14 signaling can be achieved only with FR900359 (FR) and YM-254890 (YM), two naturally occurring cyclic depsipeptides. To further development of FR or YM mimics for other Gα subunits, we here set out to rationally design Gα16 proteins with artificial FR/YM sensitivity by introducing an engineered depsipeptide-binding site. Thereby we permit control of G16 function through ligands that are inactive on the WT protein. Using CRISPR/Cas9-generated Gαq/Gα11-null cells and loss- and gain-of-function mutagenesis along with label-free whole-cell biosensing, we determined the molecular coordinates for FR/YM inhibition of Gq and transplanted these to FR/YM-insensitive G16. Intriguingly, despite having close structural similarity, FR and YM yielded biologically distinct activities: it was more difficult to perturb Gq inhibition by FR and easier to install FR inhibition onto G16 than perturb or install inhibition with YM. A unique hydrophobic network utilized by FR accounted for these unexpected discrepancies. Our results suggest that non-Gq/11/14 proteins should be amenable to inhibition by FR scaffold-based inhibitors, provided that these inhibitors mimic the interaction of FR with Gα proteins harboring engineered FR-binding sites.
Indexed as
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.