Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity
Zhangsong Wu,
Chen Qiu,
Yiming Liu,
Xiaoyi Yan,
Qiaohui Li,
Shirui Jiang,
Jun Xu,
Xin Pan,
Fang Ye,
Zhiyi Zhang,
Peiruo Ning,
Binghao Zhang,
Lezhi Xu,
Bangning Cheng,
Xufu Xiang,
Chungen Qian,
Yang Du,
Geng Chen
Affiliations
Zhangsong Wu
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China; The Huanan Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, China
Chen Qiu
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Yiming Liu
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Xiaoyi Yan
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Qiaohui Li
Biological Science Research Center, Academy for Advanced Interdisciplinary Studies, Southwest University, Chongqing, China
Shirui Jiang
The Huanan Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, China
Jun Xu
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA
Xin Pan
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Fang Ye
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Zhiyi Zhang
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Peiruo Ning
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Binghao Zhang
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Lezhi Xu
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Bangning Cheng
Department of Reagent Research and Development, Shenzhen YHLO Biotech Co., Ltd., Shenzhen, Guangdong, China
Xufu Xiang
Department of Reagent Research and Development, Shenzhen YHLO Biotech Co., Ltd., Shenzhen, Guangdong, China
Chungen Qian
Department of Reagent Research and Development, Shenzhen YHLO Biotech Co., Ltd., Shenzhen, Guangdong, China; Corresponding author
Yang Du
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China; Corresponding author
Geng Chen
Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China; Corresponding author
Summary: Prolactin-releasing peptide receptor (PrRPR), a notable member of the class A peptide-GPCR (G-protein-coupled receptor) family, regulates diverse physiology functions upon activation by PrRP. Herein, we reveal that PrRPR could engage with not only the Gq/11 pathway but also the Gi/o pathway. We further resolve the structures of the PrRPR-Gq and PrRPR-Gi complexes using cryoelectron microscopy (cryo-EM), with PrRP31 as the endogenous ligand. These high-resolution structures enhance our understanding of PrRPR-ligand interactions, aiding the development of targeted drugs aiming at this crucial peptide-receptor system. Comparing these structures with counterparts of other RF-amide peptide receptors accentuates the crucial function of the RF-amide motif in activating receptors and sheds light on the universal mechanism for RF-amide motif detection by RF-amide receptors. Furthermore, structural and functional analysis indicates that conformational alterations in the intracellular loops (ICLs), along with the “wavy hook” of Gα, may explain the selective coupling of G proteins in PrRPR signaling.
