Fig. 5. Rational design of ligands with desired signaling profiles.

(A) The addition of a single connecting methylene group to the phenyl moiety of AngII ligand restrains the C-terminal ring to remain vertical, producing a strongly arrestin-biased ligand, Ind8-AngII, which barely couples to Gq. (B) S1I8 has partial activity toward both the Gq-mediated and β-arrestin-mediated pathways. S1A2I8, which was designed to increase Gq signaling relative to S1I8 by favoring outward motion of TM6 in the binding pocket, shows increased Gq efficacy without any corresponding increase in β-arrestin efficacy. S1A2I8 is the R2A mutant of S1I8. Error bars represent standard error from 3–4 independent experiments. See also Table S2.