Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors

Jia Duan, Dan-Dan Shen, Tingting Zhao, Shimeng Guo, Xinheng He, Wanchao Yin, Peiyu Xu, Yujie Ji, Li-Nan Chen, Jinyu Liu, Huibing Zhang, Qiufeng Liu, Yi Shi, Xi Cheng, Hualiang Jiang, H. Eric Xu (), Yan Zhang (), Xin Xie () and Yi Jiang ()
Additional contact information
Jia Duan: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Dan-Dan Shen: Zhejiang University School of Medicine, Hangzhou
Tingting Zhao: School of Chinese Materia Medica, Nanjing University of Chinese Medicine
Shimeng Guo: School of Chinese Materia Medica, Nanjing University of Chinese Medicine
Xinheng He: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Wanchao Yin: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Peiyu Xu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yujie Ji: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Li-Nan Chen: Zhejiang University School of Medicine, Hangzhou
Jinyu Liu: School of Chinese Materia Medica, Nanjing University of Chinese Medicine
Huibing Zhang: Zhejiang University School of Medicine, Hangzhou
Qiufeng Liu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yi Shi: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xi Cheng: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hualiang Jiang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
H. Eric Xu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine, Hangzhou
Xin Xie: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yi Jiang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Peptide hormones and neuropeptides are complex signaling molecules that predominately function through G protein-coupled receptors (GPCRs). Two unanswered questions remaining in the field of peptide-GPCR signaling systems pertain to the basis for the diverse binding modes of peptide ligands and the specificity of G protein coupling. Here, we report the structures of a neuropeptide, galanin, bound to its receptors, GAL1R and GAL2R, in complex with their primary G protein subtypes Gi and Gq, respectively. The structures reveal a unique binding pose of galanin, which almost ‘lays flat’ on the top of the receptor transmembrane domain pocket in an α-helical conformation, and acts as an ‘allosteric-like’ agonist via a distinct signal transduction cascade. The structures also uncover the important features of intracellular loop 2 (ICL2) that mediate specific interactions with Gq, thus determining the selective coupling of Gq to GAL2R. ICL2 replacement in Gi-coupled GAL1R, μOR, 5-HT1AR, and Gs-coupled β2AR and D1R with that of GAL2R promotes Gq coupling of these receptors, highlighting the dominant roles of ICL2 in Gq selectivity. Together our results provide insights into peptide ligand recognition and allosteric activation of galanin receptors and uncover a general structural element for Gq coupling selectivity.

Date: 2022
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DOI: 10.1038/s41467-022-29072-3

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