Cell-permeable high-affinity tracers for G q proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors
Kuschak M., Namasivayam V., Rafehi M., Voss JH., Garg J., Schlegel JG.
Animal Study, published in Br J Pharmacol (2020) — summary generated from the PubMed abstract.
Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.
- Level A · Stronger Clinical Evidence
- Level B · Emerging clinical evidence with positive signals
- Level C · Early human research exploring benefits
- Level D · Scientific groundwork from lab and animal studies
- Emerging · Emerging topic under active research
This page is generated from the PubMed record. The Thai description is an automated summary of bibliographic fields and the abstract, not a full translation, and is not medical advice.
- Study type
- Animal Study
- Journal
- Br J Pharmacol (2020)
- Reported sample size
- —
- Source database
- Europe PMC
- PMID
- 31881095
- PMCID
- PMC7070167
- DOI
- 10.1111/bph.14960
- Citations
- 21
Abstract (original English)
Background and purpose G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The G q protein subtypes, which are coupled to PLC activation, can act as oncogenes, and their expression was reported to be up-regulated in cancer and inflammatory diseases. G q inhibition may be an efficient therapeutic strategy constituting a new level of intervention. However, diagnostic tools and therapeutic drugs for G q proteins are lacking. Experimental approach We have now developed G q -specific, cell-permeable 3 H-labelled high-affinity probes based on the macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM). The tracers served to specifically label and quantify G q proteins in their native conformation in cells and tissues with high accuracy. Key results FR and YM displayed low nanomolar affinity for Gα q , Gα 11 and Gα 14 expressed in CRISPR/Cas9 Gα q -knockout cells, but not for Gα 15 . The two structurally very similar tracers showed strikingly different dissociation kinetics, which is predicted to result in divergent biological effects. Computational studies suggested a "dowel" effect of the pseudoirreversibly binding FR. A high-throughput binding assay led to the discovery of novel G q inhibitors, which inhibited G q signalling in recombinant cells and primary murine brown adipocytes, resulting in enhanced differentiation. Conclusions
What this study does not prove
- • This study does not prove SVF is an approved treatment or a replacement for standard care.
- • This is preclinical work; animal or laboratory results cannot be applied to humans.
Evidence level
Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.
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