A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator
Summary
Approximately one-third of clinical drugs mediate their therapeutic effects through G protein-coupled receptors (GPCRs), highlighting their immense therapeutic relevance. Novel approaches to modulate GPCR activity have the potential to yield unique pharmacological profiles. Conventionally, the G protein and β-arrestin signaling pathways downstream of GPCRs have been viewed as mutually exclusive. Using the in-house developed survival pressure selection (SPS) method, a high-throughput platfo
Content
# A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator
*Published: 2026 Mar 5*
Approximately one-third of clinical drugs mediate their therapeutic effects
through G protein-coupled receptors (GPCRs), highlighting their immense
therapeutic relevance. Novel approaches to modulate GPCR activity have the
potential to yield unique pharmacological profiles. Conventionally, the G
protein and β-arrestin signaling pathways downstream of GPCRs have been viewed
as mutually exclusive. Using the in-house developed survival pressure selection
(SPS) method, a high-throughput platform for GPCR agonist discovery, we
identified an allosteric ligand that stabilizes a GPCR-G protein-β-arrestin
megacomplex, thereby mediating sustained receptor signaling following
internalization. Remarkably, this compound, atazanavir, exhibits pan-receptor
activation across multiple family A GPCRs, including GPR119, β1AR, and β2AR,
demonstrating the broad applicability of this regulatory mechanism. This
discovery uncovers a distinct mechanism of GPCR regulation, opening alternative
avenues for the development of therapeutics targeting GPCRs.
DOI: 10.1016/j.cell.2025.12.023