Journal Article

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

Shi, Yi, Yin, Wanchao, Liu, Qiufeng, Liu, Jinyu, Eric Xu, H., He, Xinheng, Zhang, Huibing, Shen, Dan-Dan, Jiang, Yi, Xu, Peiyu, Zhao, Tingting, Guo, Shimeng, Cheng, Xi, Duan, Jia, Ji, Yujie, Zhang, Yan, Chen, Li-Nan, Xie, Xin, Jiang, Hualiang

2022

Overview

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 G i and G q , 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 G q , thus determining the selective coupling of G q to GAL2R. ICL2 replacement in G i -coupled GAL1R, μOR, 5-HT 1A R, and G s -coupled β 2 AR and D1R with that of GAL2R promotes G q coupling of these receptors, highlighting the dominant roles of ICL2 in G q selectivity. Together our results provide insights into peptide ligand recognition and allosteric activation of galanin receptors and uncover a general structural element for G q coupling selectivity. The basis for the diverse peptide-binding modes and the G protein selectivity of peptide GPCRs remains elusive. Here, the authors offer a structural basis for allosteric-like agonism and G protein selectivity of a neuropeptide GPCR, galanin receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 13/95 / 631/45/611 / 631/535/1258/1259 / 82/16 / 82/80 / 82/83 / Allosteric properties / Binding / Coupling (molecular) / G protein-coupled receptors / Galanin / Galanin - metabolism / Galanin receptors / GTP-Binding Proteins - metabolism / Hormones / Humanities and Social Sciences / Ligands / multidisciplinary / Neuropeptides / Peptide hormones / Peptides / Protein Binding / Protein structure / Proteins / Receptor mechanisms / Receptors / Receptors, G-Protein-Coupled - metabolism / Receptors, Galanin - metabolism / Science / Science (multidisciplinary) / Selectivity / Serotonin S1 receptors / Signal Transduction / Signalling systems / Structural members