G protein-coupled receptors (GPCRs) are versatile membrane proteins. GPCRs initiate cascades of intracellular signaling events in response to an extraordinary array of extracellular signals. TRV056 is a Gq-biased ligand of the angiotensin II receptor type 1 (AT1R).
The angiotensin II type 1 receptor (AT1R) is a particularly compelling model of biased agonism in cellular signaling and in vitro transducer coupling assays. TRV056 is a Gq-biased AT1R agonist. Compared to the endogenous ligand angiotensin II (AngII), “Gq-biased” AT1R agonists are more efficacious in stimulating Gq-mediated cellular signaling and in allosterically promoting Gq coupling. However, they have comparable efficacy towards β-arrestin. In contrast, “β-arrestin-biased” ligands are deficient in Gq-mediated cellular signaling and allosteric coupling to Gq, yet they retain efficacy towards β-arrestin. Physiologically, Gq-mediated AT1R signaling increases blood pressure, while β-arrestin signaling increases cardiac contractility and performance. TRV056 is efficacious in stimulating cellular Gq-mediated signaling.
“Biased” G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Compared to angiotensin II, the endogenous agonist, agonists with enhanced Gq coupling more strongly stabilize an “open” conformation with an accessible transducer-binding site. TRV056 is a “gain-of-function” ligand that has >10-fold greater allosteric coupling to Gq than AngII and is also more efficacious in stimulating cellular Gq-mediated signaling (e.g., IP1 generation), but they show similar allosteric coupling to β-arrestin as AngII. TRV056 leads to distance distributions that are very similar to each other but quite distinct from those induced by AngII.
All in all, TRV056 is a Gq-biased ligand of the angiotensin II receptor type 1 (AT1R). TRV056 is efficacious in stimulating cellular Gq-mediated signaling.
Laura M Wingler, et al. Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. Cell. 2019 Jan 24;176(3):468-478.e11.