7WZ4

Structure of an orphan GPCR-G protein signaling complex

Summary for 7WZ4

• Entry DOI: 10.2210/pdb7wz4/pdb
• Related: 7EJX
• EMDB information: 32904
• Descriptor: Probable G-protein coupled receptor 88, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• Functional Keywords: gpr88, signaling complex, cryo-em, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 171045.89

Authors

Xu, J.,Chen, G.,Liu, Z.,Du, Y. (deposition date: 2022-02-17, release date: 2022-10-26, Last modification date: 2024-10-16)

Primary citation

Chen, G.,Xu, J.,Inoue, A.,Schmidt, M.F.,Bai, C.,Lu, Q.,Gmeiner, P.,Liu, Z.,Du, Y.
Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex.
Nat Commun, 13:2375-2375, 2022

PubMed 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.

PubMed: 35501348
DOI: 10.1038/s41467-022-30081-5

Experimental method

ELECTRON MICROSCOPY (3 Å)