Computational characterization of transducer recognition of β2 adrenergic receptor

As an important drug target, β2 adrenergic receptor (B2AR) regulates many physiological processes, including cardiac function, airway tone and metabolic functions. The selective coupling between B2AR and specific transducers is critical for the physiological action of the receptor. However, the molecular mechanism by which B2AR recognizes different transducers remains elusive. Here, molecular dynamics simulations of B2AR binding to three functionally important transducers (Gs, Gi and β-arrestin 1) unveiled distinct binding modes of the receptor. Involving transmembrane helices TMs 2-7 and intracellular loops ICLs 2-3, different binding interfaces for Gs and β-arrestin 1 were identified in the simulation models and further validated by various assays. The distinct recognition mode of B2AR for Gi was computationally characterized. Insights into receptor-transducer communication not only enhance our understanding of signaling bias, but also offer hints for rational drug design targeting specific signaling pathways of G-protein coupled receptors (GPCRs).