Molecular insights into ligand recognition and G protein coupling of the neuromodulatory orphan receptor GPR139

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The G protein-coupled receptor GPR139 is involved in neuromodulation, and one of its agonists is in clinical trials for the treatment of cognitive impairment and negative symptoms of schizophrenia. While GPR139 is a understudied ‘orphan’ receptor, it can be activated by the amino acids L-Trp, L-Phe1 or α-Melanocyte-stimulating hormone (α-MSH) which is an endogenous agonist of melanocortin receptors.2,3 GPR139 activation triggers several G protein pathways of which Gq/11 is the primary.4,5,6,7 Of note, the expression of GPR139 correlates with that of the μ-opioid and dopamine D2 receptors in a broad range of the central nervous system (CNS), which acts as a regulator of μ-opioid and dopamine signaling.6,7,8,9 For example, GPR139 antagonist JNJ-3792165 increases the sensitivity of the μ-opioid receptor to morphine.6 Hitherto, the structural basis of how ligands interact with and activate GPR139 to transduce diverse signals has remained unknown. Furthermore, the more physiologically relevant intermediate states of GPCR–G protein complex structures in the nucleotide-bound forms are also elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of GPR139 in complex with a key reference ligand JNJ-63533054 which is an analog of agent TAK-04110 in clinical trial, and miniGs/q or Gi in nucleotide-free form, as well as the GPR139–JNJ-63533054–miniGs/q complex in GDP- and GTP-bound states, respectively (Fig. 1a–f).
Original languageEnglish
JournalCell Research
Issue number2
Pages (from-to)210-213
Publication statusPublished - 2022

Bibliographical note

Funding Information:
This work was supported by the CAS Strategic Priority Research Program XDB37030104 (Z.-J.L.), the National Science Fund for Distinguished Young Scholars 32022038 (T.H.), the National Natural Science Foundation of China grants 31930060 (Z.-J.L.) and 31870744 (T.H.), and the Shanghai Rising-Star Program 20QA1406500 (T. H.), the Lundbeck Foundation R163-2013-16327 (D.E.G.), the Novo Nordisk Foundation NNF18OC0031226 (D.E.G.) and Independent Research Fund Denmark | Natural Sciences 8021-00173B (D.E.G.), the Lundbeck Foundation R355-2020-949 (B.T.) and the Carlsberg Foundation CF20-0248 (H.B.-O.). D.E.G. is a member of the Integrative Structural Biology at the University of Copenhagen (ISBUC). The cryo-EM data were collected at the Bio-Electron Microscopy Facility, ShanghaiTech University, with the assistance of Q.-Q. Sun, D.-D. Liu, Z.-H. Zhang and Y.-H. Liu. We thank the Assay Core, the assistance of F.-F. Zhou and Q.-W. Tan and the Cell Expression, Cloning and Purification Core Facilities of iHuman Institute for their support.

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