Fig. 1. Computational modeling and design of GPCR associations with reprogrammed structures and functions using QUESTS.

a Framework for the modeling and design of specific receptor quaternary active state conformations eliciting various degree of functional selectivity. The WT receptor modeled in the active state is assembled into dimers and then into ternary complex with G proteins (green) or β-arrestin (orange) to identify the distribution of quaternary conformations and their ability to recruit intracellular signaling proteins. The dimer binding interface is redesigned to stabilize and/or destabilize specific quaternary conformations. This design strategy enhances the quaternary conformational selectivity of the receptor and reprograms the functional bias of the receptor oligomer (Supplementary Fig. 1, Methods). b Quaternary structural changes act as a functional switch as the closed-dimer conformation interferes with the binding of a GPCR monomer to β-arrestin.