%0 Journal Article
%T Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide
%A Li Xin
%A Li Shuai
%A Shan Hong
%A Yuan Qing-ning
%A He Xin-heng
%A He Qian
%A Zhang Min
%A Li Yang
%A Hu Wen
%A Wu Kai
%A Xu H. Eric
%A Zhao Li-hua
%J Acta Pharmacologica Sinica
%D 2026
%B 2026
%9 
%! Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide
%K 
%X 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-Gαq and NPFF2R-Gαi 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-Gαi 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.
%U http://www.chinaphar.com/article/view/11546
%V 47
%N 6
%P 1671-1681
%@ 1745-7254