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

Zhou, Yali; Daver, Henrik; Trapkov, Boris; Wu, Lijie; Wu, Meng; Harpsøe, Kasper; Gentry, Patrick R.; Liu, Kaiwen; Larionova, Marina D.; Liu, Junlin; Chen, Na; Bräuner‐Osborne, Hans; Gloriam, David E.; Hua, Tian; Liu, Zhijie

doi:10.1038/s41422-021-00591-w

Cited by 18 publications

(11 citation statements)

References 17 publications

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“…We selected the reported GPR139 agonists JNJ-63533054 and TAK-041 as the lead compounds for optimization, hoping to obtain GPR139 agonists with higher functional potency. The reported binding pose of JNJ-63533054 and docking pose of TAK-041 at GPR139 (Figure B) showed that both compounds bind with a bent conformation around the arginine residue R244 6.51 . The left-hand phenyl group of JNJ-63533054 and the benzo[ d ][1,2,3]triazin-4(3 H )-one moiety of TAK-041 point to a shallow hydrophobic pocket and form π–π interactions with the tryptaphan residue W170 ECL2 .…”

Section: Resultsmentioning

confidence: 99%

“…The reported binding pose of JNJ-63533054 and docking pose of TAK-041 at GPR139 (Figure 1B) showed that both compounds bind with a bent conformation around the arginine residue R244 6.51 . 36 The left-hand phenyl group of JNJ-63533054 and the benzo[d]-[1,2,3]triazin-4(3H)-one moiety of TAK-041 point to a shallow hydrophobic pocket and form π−π interactions with the tryptaphan residue W170 ECL2 . The right-hand phenyl group of both compounds point downward into a deep hydrophobic pocket, forming cation−π interactions with R244 6.51 and π−π interactions with W241 6.48 .…”

Section: ■ Introductionmentioning

confidence: 99%

“…35 Very recently, Zhou et al reported the cryogenic electron microscopy (cryo-EM) structures of GPR139 in complex with JNJ-63533054, which provided important information for structure-based design of novel GPR139 agonists. 36 In order to obtain novel and potent GPR139 agonists with desirable pharmacokinetic properties and drug-like profiles, we designed and synthesized a series of GPR139 agonists using compound TAK-041 as a lead structure. The structure−activity relationships (SARs) of these compounds, as well as their pharmacokinetic properties and in vivo efficacy in schizophrenia-like murine behavioral models are reported herein.…”

Section: ■ Introductionmentioning

confidence: 99%

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Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Mao,

Cui,

Wang

et al. 2023

J. Med. Chem.

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The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC50 = 31.4 nM) and 20a (EC50 = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Mao,

Cui,

Wang

et al. 2023

J. Med. Chem.

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“…Orphan G protein-coupled receptors (oGPCRs) are pathologically related to many human diseases such as schizophrenia, type 2 diabetes, hyperactivity, cognitive impairment, brain malformation, Alzheimer's disease and others [1][2][3][4][5][6][7] . Many oGPCRs including the adhesion family (aGPCRs) are constitutively active receptors, presenting additional technical hurdles for deorphanization 8 .…”

Section: Introductionmentioning

confidence: 99%

The activation mechanism and antibody binding mode for orphan GPR20

Lin

Jiang

et al. 2023

Cell Discov

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GPR20 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for gastrointestinal stromal tumors (GIST) owing to its differentially high expression. An antibody-drug conjugate (ADC) containing a GPR20-binding antibody (Ab046) was recently developed in clinical trials for GIST treatment. GPR20 constitutively activates Gi proteins in the absence of any known ligand, but it remains obscure how this high basal activity is achieved. Here we report three cryo-EM structures of human GPR20 complexes including Gi-coupled GPR20 in the absence or presence of the Fab fragment of Ab046 and Gi-free GPR20. Remarkably, the structures demonstrate a uniquely folded N-terminal helix capping onto the transmembrane domain and our mutagenesis study suggests a key role of this cap region in stimulating the basal activity of GPR20. We also uncover the molecular interactions between GPR20 and Ab046, which may enable the design of tool antibodies with enhanced affinity or new functionality for GPR20. Furthermore, we report the orthosteric pocket occupied by an unassigned density which might be essential for exploring opportunities for deorphanization.

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“…Recently, Moro’s group ( 31 ) provided the supervised MD (SuMD) approach, which combined a tabu-like supervision algorithm on the ligand–receptor approaching distance with cMD simulations, to study the binding event and pathway between an antagonist and A 2A R at dozens of nanoseconds. Moreover, with the emergence of active X-ray or cryo-EM structures of GPCRs, many cMD and enhanced sampling MD simulations have been shown to be successful in studying the activation mechanism of GPCRs ( 25 , 32 – 36 ). However, MD studies focusing on the interaction between GPCRs and intracellular proteins are scarce, even though many GPCRs combined with intracellular proteins have been resolved experimentally.…”

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confidence: 99%

The full activation mechanism of the adenosine A ₁ receptor revealed by GaMD and Su-GaMD simulations

Sun

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The full activation process of G protein–coupled receptor (GPCR) plays an important role in cellular signal transduction. However, it remains challenging to simulate the whole process in which the GPCR is recognized and activated by a ligand and then couples to the G protein on a reasonable simulation timescale. Here, we developed a molecular dynamics (MD) approach named supervised (Su) Gaussian accelerated MD (GaMD) by incorporating a tabu-like supervision algorithm into a standard GaMD simulation. By using this Su-GaMD method, from the active and inactive structure of adenosine A 1 receptor (A 1 R), we successfully revealed the full activation mechanism of A 1 R, including adenosine (Ado)–A 1 R recognition, preactivation of A 1 R, and A 1 R–G protein recognition, in hundreds of nanoseconds of simulations. The binding of Ado to the extracellular side of A 1 R initiates conformational changes and the preactivation of A 1 R. In turn, the binding of G i2 to the intracellular side of A 1 R causes a decrease in the volume of the extracellular orthosteric site and stabilizes the binding of Ado to A 1 R. Su-GaMD could be a useful tool to reconstruct or even predict ligand–protein and protein–protein recognition pathways on a short timescale. The intermediate states revealed in this study could provide more detailed complementary structural characterizations to facilitate the drug design of A 1 R in the future.

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

Cited by 18 publications

References 17 publications

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

The activation mechanism and antibody binding mode for orphan GPR20

The full activation mechanism of the adenosine A ₁ receptor revealed by GaMD and Su-GaMD simulations

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

Cited by 18 publications

References 17 publications

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

The activation mechanism and antibody binding mode for orphan GPR20

The full activation mechanism of the adenosine A 1 receptor revealed by GaMD and Su-GaMD simulations

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The full activation mechanism of the adenosine A ₁ receptor revealed by GaMD and Su-GaMD simulations