Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
Chen G, Xu J, Inoue A, Schmidt M, Bai C, Lu Q, Gmeiner P, Liu Z, Du Y (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 13
Article Number: 2375
Journal Issue: 1
DOI: 10.1038/s41467-022-30081-5
Abstract
GPR88 is an orphan class A G-protein-coupled receptor that is highly expressed in the striatum and regulates diverse brain and behavioral functions. Here we present cryo-EM structures of the human GPR88-Gi1 signaling complex with or without a synthetic agonist (1R, 2R)-2-PCCA. We show that (1R, 2R)-2-PCCA is an allosteric modulator binding to a herein identified pocket formed by the cytoplasmic ends of transmembrane segments 5, 6, and the extreme C terminus of the α5 helix of Gi1. We also identify an electron density in the extracellular orthosteric site that may represent a putative endogenous ligand of GPR88. These structures, together with mutagenesis studies and an inactive state model obtained from metadynamics simulations, reveal a unique activation mechanism for GPR88 with a set of distinctive structure features and a water-mediated polar network. Overall, our results provide a structural framework for understanding the ligand binding, activation and signaling mechanism of GPR88, and will facilitate the innovative drug discovery for neuropsychiatric disorders and for deorphanization of this receptor.
Authors with CRIS profile
Maximilian Schmidt
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
China (CN)
Japan (JP)How to cite
APA:
Chen, G., Xu, J., Inoue, A., Schmidt, M., Bai, C., Lu, Q.,... Du, Y. (2022). Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. Nature Communications, 13(1). https://dx.doi.org/10.1038/s41467-022-30081-5
MLA:
Chen, Geng, et al. "Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex." Nature Communications 13.1 (2022).
BibTeX: Download