9V0X

Cryo-EM structure of Gq-coupled PrRPR in complex with GUB08248

Summary for 9V0X

• Entry DOI: 10.2210/pdb9v0x/pdb
• EMDB information: 64674
• Descriptor: Guanine nucleotide-binding protein G(324) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, scFv16, ... (7 entities in total)
• Functional Keywords: prolactin-releasing peptide, prrpr, complex, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 159058.48

Authors

Zhao, L.,Li, X.,Li, S.,Yuan, Q.,Xu, H.E. (deposition date: 2025-05-19, release date: 2026-02-04, Last modification date: 2026-02-18)

Primary citation

Li, X.,Li, S.,Shan, H.,Yuan, Q.N.,He, X.H.,He, Q.,Zhang, M.,Li, Y.,Hu, W.,Wu, K.,Xu, H.E.,Zhao, L.H.
Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide.
Acta Pharmacol.Sin., 2026

PubMed Abstract: Prolactin-releasing peptide (PrRP) is an endogenous ligand for the PrRPR, whose activation has been linked to anti-obesity effects. However, PrRP and its analogs also activate the neuropeptide FF receptor 2 (NPFF2R), which is associated with adverse cardiovascular effects. Understanding how PrRP-related peptides differentially engage these two distinct receptors is critical for developing safer, more selective therapeutics. In this study, we present cryo-EM structures of the PrRP analog GUB08248 bound to PrRPR-Gα and NPFF2R-Gα at resolutions of 2.45 Å and 2.85 Å, respectively. These structures reveal a conserved ligand recognition mode across both receptors, while highlighting distinct receptor-specific interactions. The NPFF2R-Gα complex further uncovers key features of receptor activation and G protein coupling. Together, our results offer structural insights that could guide structure-based drug design strategies favoring PrRPR selectivity, thereby advancing the therapeutic potential of the PrRP-PrRPR axis for obesity treatment.

PubMed: 41639321
DOI: 10.1038/s41401-025-01741-1

Experimental method

ELECTRON MICROSCOPY (2.66 Å)