A GPCR-G protein-β-arrestin megacomplex induced by an allosteric modulator

GPCRs signal through both G protein pathways and β-arrestin pathways. Previous work suggests that β-arrestins bind to GPCRs through different modes, including core engagement and tail engagement. Core engagement competes with G proteins and terminates G protein signaling, while tail engagement can coexist with G proteins, mediating sustained intracellular activation of the receptor – a process dependent on the high affinity between β-arrestin and the phosphorylated C-terminus of the receptor. In this study, we determined the structure of a GPCR - G protein - β-arrestin-1 complex stabilized by an allosteric modulator. The compound, atazanavir, acts like molecular glue to anchor β-arrestin-1 to the receptor’s TM6 and TM7 regions. This ‘pendulum’ binding mode is structurally compatible with simultaneous G protein binding. We further demonstrate that the atazanavir-mediated β-arrestin recruitment does not require the receptor’s C-terminal region. This work illustrates a novel paradigm of GPCR-G protein-β-arrestin1 megacomplex assembly and opens up new avenues for modulating GPCR function.