9K0X

Cryo-EM structure of ATP-bound P2Y purinoceptor 2-miniGq-Nb35 complex

Summary for 9K0X

• Entry DOI: 10.2210/pdb9k0x/pdb
• EMDB information: 61958
• 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, ... (6 entities in total)
• Functional Keywords: g protein-coupled receptors, g-protein signaling, nucleotide receptors, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 137541.23

Authors

Lan, B.,Zhang, S.,Liu, X.,Lin, B. (deposition date: 2024-10-16, release date: 2025-06-11)

Primary citation

Lan, B.,Zhang, S.,Chen, K.,Dai, S.,Fei, J.,Gao, K.,Sun, X.,Lin, B.,Liu, X.
Structural insight into the self-activation and G-protein coupling of P2Y2 receptor.
Cell Discov, 11:47-47, 2025

PubMed Abstract: Purinergic P2Y2 receptor (P2Y2R) represents a typically extracellular ATP and UTP sensor for mediating purinergic signaling. Despite its importance as a pharmacological target, the molecular mechanisms underlying ligand recognition and G-protein coupling have remained elusive due to lack of structural information. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the apo P2Y2R in complex with G, ATP-bound P2Y2R in complex with G or G, and UTP-bound P2Y4R in complex with G. These structures reveal the similarities and distinctions of ligand recognition within the P2Y receptor family. Furthermore, a comprehensive analysis of G-protein coupling reveals that P2Y2R exhibits promiscuity in coupling with both G and G proteins. Combining molecular dynamics simulations and signaling assays, we elucidate the molecular mechanisms by which P2Y2R differentiates pathway-specific G or G coupling through distinct structural components on the intracellular side. Strikingly, we identify a helix-like segment within the N-terminus that occupies the orthosteric ligand-binding pocket of P2Y2R, accounting for its self-activation. Taken together, these findings provide a molecular framework for understanding the activation mechanism of P2Y2R, encompassing ligand recognition, G-protein coupling, and a novel N-terminus-mediated self-activation mechanism.

PubMed: 40360475
DOI: 10.1038/s41421-025-00797-x

Experimental method

ELECTRON MICROSCOPY (2.83 Å)