9L84

Structure of beta1-AR-Gs complex bound to epinephrine and an allosteric modulator

Summary for 9L84

• Entry DOI: 10.2210/pdb9l84/pdb
• EMDB information: 62884
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Bos taurus (domestic cattle); More
• Total number of polymer chains: 5
• Total formula weight: 159382.00

Authors

Sun, Q.,He, G.,Xu, X.,Liu, X. (deposition date: 2024-12-27, release date: 2025-12-31, Last modification date: 2026-07-15)

Primary citation

He, G.,Sun, Q.,Xu, X.,Kong, F.,Zhang, S.,Ye, K.,Sun, X.,Lin, B.,Chen, X.,Yan, C.,Liu, X.
A GPCR-G protein-beta-arrestin megacomplex enabled by a versatile allosteric modulator.
Cell, 189:1434-1450.e22, 2026

PubMed Abstract: 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, βAR, and βAR, 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.

PubMed: 41605208
DOI: 10.1016/j.cell.2025.12.023

Experimental method

ELECTRON MICROSCOPY (3.22 Å)