Volume 32, No 2, Feb 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 2, February 2022: 210-213   |  Open Access

LETTERS TO THE EDITOR

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

Yali Zhou^1,2,3,4 , Henrik Daver⁵ , Boris Trapkov⁵ , Lijie Wu¹ , Meng Wu¹ , Kasper Harpsøe⁵ , Patrick R. Gentry⁵ , Kaiwen Liu¹ , Marina Larionova^1,6 , Junlin Liu¹ , Na Chen¹ , Hans Bräuner-Osborne^5,* , David E. Gloriam^5,* , Tian Hua^1,2,* , Zhi-Jie Liu^1,2,*

¹iHuman Institute, ShanghaiTech University, Shanghai, China
²School of Life Science and Technology, ShanghaiTech University, Shanghai, China
³University of Chinese Academy of Sciences, Beijing, China
⁴CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
⁵Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark
⁶Photobiology laboratory, Institute of Biophysics SB RAS, Federal Research Center “Krasnoyarsk Science Center SB RAS”, Akademgorodok 50/50, Krasnoyarsk, Russia
Correspondence: Hans Bräuner-Osborne(hbo@sund.ku.dk)David E. Gloriam(david.gloriam@sund.ku.dk)Tian Hua(huatian@shanghaitech.edu.cn)Zhi-Jie Liu(liuzhj@shanghaitech.edu.cn)

Dear Editor,

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 a

https://doi.org/10.1038/s41422-021-00591-w

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