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The mechanism of negative symptoms of anti-schizophrenia and the safety of opioids have always been scientific problems that need to be solved urgently
.
The orphan receptor GPR139 is a highly expressed G protein-coupled receptor (GPCR) in the brain, which is highly correlated with the expression of μ opioid receptors and dopamine receptors (D2R), and participates in the body Basic life activities such as regulation and exercise metabolism
.
Studies have shown that GPR139 is closely related to the occurrence and development of many central nervous system diseases such as schizophrenia, Parkinson's disease, and alcohol addiction
.
At present, the small molecule TAK-041, an agonist for GPR139, has entered clinical phase I trials for the treatment of negative symptoms of schizophrenia
.
At the same time, studies have also found that GPR139 has a negative regulatory effect on mu opioid receptor signals, and GPR139 antagonists are expected to improve the safety of opioids
.
Therefore, the study of ligand regulation and signal transduction molecular mechanism of GPR139 has very important guiding significance for future basic and translational research
.
Recently, the Liu Zhijie/Hua Tian team from the iHuman Institute of Shanghai University of Science and Technology and collaborators from the University of Copenhagen in Denmark published an online research paper entitled "Molecular insights into ligand recognition and G protein coupling of the neuromodulatory orphan receptor GPR139" on Cell Research, revealing The three-dimensional structure of GPR139, small molecule agonists and different downstream signal transduction proteins Gq and Gi complexes are revealed, which reveals the regulation mechanism of agonists, and provides a precise template for structure-based targeted drug design and optimization
.
At the same time, the study also reported the structure of the GPR139-Gq complex that binds to GDP- and GTP-, respectively, expounding for the first time the regulatory mechanism of G protein on GPCR in the state of GTP and GDP binding
.
As an orphan receptor, GPR139's endogenous ligand and receptor activation mechanism are still unclear
.
With the technical support of the bioelectron microscope platform of Shanghai University of Science and Technology, the research team analyzed the structure of the GPR139-Gq and GPR139-Gi complex combined with the agonist JNJ-63533054
.
It is the first time to reveal the binding pocket of the small agonist molecule JNJ-63533054 and the unique activation mechanism of GPR139, as well as the interaction mode of GPR139 with different G proteins
.
The research team further combined molecular docking and pharmacological studies to explore the binding mode of clinical candidate drug molecule TAK-041 and the regulation mechanism of different GPR139 signaling pathways, providing a scientific basis for the development of innovative drugs for GPR139
.
The structure of the GPCR-G protein complex that has been analyzed so far, the G protein is in a nuclearide free state
.
How the nucleotide bound G protein regulates GPCR under physiological conditions is still unknown
.
Due to the highly dynamic nature of this regulatory process, it is difficult to obtain stable composite samples for structural biology research
.
The researchers successfully captured the GDP- and GTP-bound GPR139-Gq complex by adding GDP or GTP before freezing samples
.
Through structural analysis and comparison, it revealed the molecular mechanism of GPCR regulation by G protein closer to the physiological state, and further deepened the understanding of GPCR-mediated cell signal transduction
.
The signal transduction mode of GPR139 and the three-dimensional fine structure of different downstream G protein complexes.
Zhou Yali, a 2019 PhD student in the School of Life Sciences, ShanghaiTech University, is the first author of the paper; Dean of the Dadao Academy of ShanghaiTech University and Executive Director of the iHuman Institute , Professor Liu Zhijie of School of Life Sciences, Assistant Professor Hua Tian of iHuman Institute and School of Life Sciences, and Professors David E.
Gloriam and Hans Bräuner-Osborne of the University of Copenhagen in Denmark are the co-corresponding authors
.
Shanghai University of Science and Technology is the first unit to complete the thesis
.
This work was funded by the National Natural Science Foundation of China, the pilot project of the Chinese Academy of Sciences, and the Shanghai Science and Technology Commission project
.
Link to the paper: https:// is open for reprinting, welcome to forward to Moments and WeChat groups
.
The orphan receptor GPR139 is a highly expressed G protein-coupled receptor (GPCR) in the brain, which is highly correlated with the expression of μ opioid receptors and dopamine receptors (D2R), and participates in the body Basic life activities such as regulation and exercise metabolism
.
Studies have shown that GPR139 is closely related to the occurrence and development of many central nervous system diseases such as schizophrenia, Parkinson's disease, and alcohol addiction
.
At present, the small molecule TAK-041, an agonist for GPR139, has entered clinical phase I trials for the treatment of negative symptoms of schizophrenia
.
At the same time, studies have also found that GPR139 has a negative regulatory effect on mu opioid receptor signals, and GPR139 antagonists are expected to improve the safety of opioids
.
Therefore, the study of ligand regulation and signal transduction molecular mechanism of GPR139 has very important guiding significance for future basic and translational research
.
Recently, the Liu Zhijie/Hua Tian team from the iHuman Institute of Shanghai University of Science and Technology and collaborators from the University of Copenhagen in Denmark published an online research paper entitled "Molecular insights into ligand recognition and G protein coupling of the neuromodulatory orphan receptor GPR139" on Cell Research, revealing The three-dimensional structure of GPR139, small molecule agonists and different downstream signal transduction proteins Gq and Gi complexes are revealed, which reveals the regulation mechanism of agonists, and provides a precise template for structure-based targeted drug design and optimization
.
At the same time, the study also reported the structure of the GPR139-Gq complex that binds to GDP- and GTP-, respectively, expounding for the first time the regulatory mechanism of G protein on GPCR in the state of GTP and GDP binding
.
As an orphan receptor, GPR139's endogenous ligand and receptor activation mechanism are still unclear
.
With the technical support of the bioelectron microscope platform of Shanghai University of Science and Technology, the research team analyzed the structure of the GPR139-Gq and GPR139-Gi complex combined with the agonist JNJ-63533054
.
It is the first time to reveal the binding pocket of the small agonist molecule JNJ-63533054 and the unique activation mechanism of GPR139, as well as the interaction mode of GPR139 with different G proteins
.
The research team further combined molecular docking and pharmacological studies to explore the binding mode of clinical candidate drug molecule TAK-041 and the regulation mechanism of different GPR139 signaling pathways, providing a scientific basis for the development of innovative drugs for GPR139
.
The structure of the GPCR-G protein complex that has been analyzed so far, the G protein is in a nuclearide free state
.
How the nucleotide bound G protein regulates GPCR under physiological conditions is still unknown
.
Due to the highly dynamic nature of this regulatory process, it is difficult to obtain stable composite samples for structural biology research
.
The researchers successfully captured the GDP- and GTP-bound GPR139-Gq complex by adding GDP or GTP before freezing samples
.
Through structural analysis and comparison, it revealed the molecular mechanism of GPCR regulation by G protein closer to the physiological state, and further deepened the understanding of GPCR-mediated cell signal transduction
.
The signal transduction mode of GPR139 and the three-dimensional fine structure of different downstream G protein complexes.
Zhou Yali, a 2019 PhD student in the School of Life Sciences, ShanghaiTech University, is the first author of the paper; Dean of the Dadao Academy of ShanghaiTech University and Executive Director of the iHuman Institute , Professor Liu Zhijie of School of Life Sciences, Assistant Professor Hua Tian of iHuman Institute and School of Life Sciences, and Professors David E.
Gloriam and Hans Bräuner-Osborne of the University of Copenhagen in Denmark are the co-corresponding authors
.
Shanghai University of Science and Technology is the first unit to complete the thesis
.
This work was funded by the National Natural Science Foundation of China, the pilot project of the Chinese Academy of Sciences, and the Shanghai Science and Technology Commission project
.
Link to the paper: https:// is open for reprinting, welcome to forward to Moments and WeChat groups
