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bioRxiv · 10.1101/2025.03.24.645131

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

He, G.·Sun, Q.·Xu, X.·Kong, F.·Zhang, S.·Ye, K.·Sun, X.·Chen, X.·Yan, C.·Liu, X.
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Abstract

GPCRs signal through both G protein pathways and {beta}-arrestin pathways. Previous work suggests that {beta}-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 {beta}-arrestin and the phosphorylated C-terminus of the receptor. In this study, we determined the structure of a GPCR - G protein - {beta}-arrestin-1 complex stabilized by an allosteric modulator. The compound, atazanavir, acts like molecular glue to anchor {beta}-arrestin-1 to the receptors TM6 and TM7 regions. This pendulum binding mode is structurally compatible with simultaneous G protein binding. We further demonstrate that the atazanavir-mediated {beta}-arrestin recruitment does not require the receptors C-terminal region. This work illustrates a novel paradigm of GPCR-G protein-{beta}-arrestin1 megacomplex assembly and opens up new avenues for modulating GPCR function.

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He, G., Sun, Q., Xu, X., Kong, F., Zhang, S., Ye, K., Sun, X., Chen, X., Yan, C., Liu, X.. 2025-03-27. A GPCR-G protein-β-arrestin megacomplex induced by an allosteric modulator. https://doi.org/10.1101/2025.03.24.645131

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