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▎Editor of WuXi AppTec's content team When you are itching unbearable due to mosquito bites, allergies or other diseases, have you ever thought about how this heart-scratching perception is formed? Early studies believed that the neural mechanisms of itching and pain are similar-the same type of neuron can cause itching when stimulated by low-frequency electrical signals; when the frequency increases, it will be converted into pain
.
However, with the deepening of research, people gradually realized that the generation of itch is more complicated and unique than previously thought
.
In 2009, the team of Professor Xinzhong Dong of Johns Hopkins University in the United States discovered that a G-coupled protein receptor (GPCR) can produce itch sensation under the stimulation of specific compounds.
This discovery opened up the itch receptor (MRGPR).
) New research field
.
This receptor was later named MRGPRX1 in the human body, unveiling the tip of the iceberg of the itch receptor family
.
After recent years of research, the itch receptor family has gradually expanded
.
From MRGPRA to MRGPRH, plus MRGPRX, a total of 9 itch receptor subfamilies were discovered, which contained more than 50 different receptors
.
For example, in the MRGPRX subfamily, there are four receptors from MRGPRX1 to MRGPRX4
.
Facing the huge and complex family of itch receptors, scientists are working hard to uncover the structural and functional information contained in them
.
This week, two papers published in Nature magazine used cryo-electron microscopy to reveal the fine three-dimensional structure of different itch receptors when combined with ligands
.
One of the papers was completed by the team of Professor Jinpeng Sun and Professor Ning Gao of Peking University.
This research focused on MRGPRX2 in the MRGPR family
.
Professor Sun Jinpeng said that his laboratory is most interested in MRGPRX2.
One reason is that many people in the laboratory have allergic reactions, including pollen allergies
.
Previous studies have found that MRGPRX2, which is mainly distributed in mast cells, can sense a variety of secretins including polycationic compounds and short peptides, causing pseudo-allergic reactions
.
How does MRGPRX2 recognize polycationic compounds and short peptides? This research gives the answer
.
It has been discovered that a variety of positively charged basic small molecules can activate MRGPRX2
.
This study resolved the structure of the complex of MRGPRX2 and Gi trimer when these small molecules act
.
It was found that the two acidic amino acids in the binding pocket of MRGPRX2 can recognize the positively charged basic groups on small molecules and thus bind to small molecules
.
In addition, the research team also found a universal sequence of short peptides that can be recognized by MRGPRX2.
Endogenous short peptides and short peptide drugs containing this sequence can activate MRGPRX2 and cause itching
.
▲Under cryo-electron microscopy, the structure formed by the combination of MRGPRX2 and ligand (picture source: Reference [1]) Scientists have noticed clinically that certain drugs will also activate the MRGPRX2 receptor, triggering the release of histamine, which induces itching Side effects
.
The discovery of this short peptide universal sequence provides an important theoretical basis for the development of drugs that can avoid this side effect
.
In addition, this study also revealed the unique activation mechanism of MRGPRX2, expanding people's understanding of the activation mechanism of the itch receptor family
.
In another paper published at the same time, researchers from the University of North Carolina at Chapel Hill and the University of California, San Francisco also used cryo-electron microscopy to analyze the molecular structure of MRGPRX2 and screened out a highly effective antagonist that can inhibit the activation of MRGPRX2
.
In addition, this study also analyzed in detail MRGPRX4, another member of the itch receptor family
.
MRGPRX4 is located on neurons that sense itching.
Previous studies have found that when this receptor is activated, it can cause pruritus in patients with liver disease cholestasis
.
▲Schematic diagram of polypeptide activation of MRGPRX2 [Image source: UNC SCHOOL OF MEDICINE (ROTH/FAY)] Why belong to the same subfamily, but MRGPRX4 cannot recognize positively charged molecules like MRGPRX2, but binds to negatively charged cholic acid? This study analyzed the structure of MRGPRX4 and found that the two acidic amino acids in MRGPRX2 were blocked by the extracellular part of the receptor, so they could not recognize positively charged molecules in MRGPRX4; on the contrary, the sequence change made the binding pocket carry Positive electricity, which also explains the itching caused by cholestasis
.
These two major studies let us see the true face of itch receptors for the first time, and laid a solid foundation for more basic research and drug development on itch
.
I believe that with more follow-up research, more mysteries about the mysterious perception of tickle will eventually be revealed
.
Experts commented on Dong Xinzhong (Johns Hopkins University, Professor of Neuroscience) Itching is a sensation that everyone can feel every day but is not very clear
.
So how exactly does itching come about? It turns out that some itch receptors in the sensory nerve endings in the skin can detect irritants on the skin that cause itching
.
In addition, some immune cells in the skin, such as mast cells, can also activate and release histamine through other itch receptors to cause itching
.
Twenty years ago, when I was a postdoctoral fellow in the laboratory of Professor David Anderson at the California Institute of Technology, I discovered a new group of G-coupled protein receptor (GPCR) subfamily.
We named it MRGPR (including 50 mouse Mrgprs).
And 8 human MRGPRs)
.
At first, we did not know what the function of MRGPRs is.
After more than ten years of joint efforts in our laboratory and other teams, we discovered that some MRGPRS are the aforementioned itch receptors on sensory nerves and mast cells.
Among them are MRGPRX2 and MRGPRX4
.
The two papers to be reviewed today are the results of research on the analysis of the three-dimensional protein structure of MRGPRX2 and MRGPRX4, which were published simultaneously in the journal Nature
.
One was completed by Sun Jinpeng's team and Peking University Gao Ning's team, and the other was completed by Bryan Roth's team from the University of North Carolina at Chapel Hill and researchers from the University of California, San Francisco
.
Analyzing the structure of MRGPRX is challenging because the protein sequence of this GPCR is very short, most of which are hidden in the cell membrane, so it is impossible to analyze the structure by protein crystallization
.
Professor Sun Jinpeng and Professor Roth are GPCR pharmacologists and cryo-electron microscopy experts.
Their two teams used this technology to analyze the high-resolution protein structures of itch receptors MRGPRX2 and MRGPRX4
.
This is the first time I have seen the appearance of itch receptors in 20 years, so I am very happy
.
The publication of these two papers is also an important milestone in the field of MRGPR research
.
MRGPRs are not the same as the familiar GPCRs
.
Most GPCRs are activated by one or two very specific ligands; while one MRGPR can be activated by many different low-affinity ligands, including small molecule compounds and short peptides
.
The best example is MRGPRX2 on mast cells
.
We found that MRGPRX2 can be activated by dozens of small molecule drugs used clinically and short peptides in the body
.
These drugs can cause mast cells to release histamine and other mediators through MRGPRX2, causing drug allergy symptoms including difficulty breathing, decreased body temperature, redness, and itching
.
So why can so many substances activate MRGPRX2? The results of these two studies perfectly explain this problem that has puzzled us for many years
.
From the protein structure, it can be clearly seen that the ligand binding pocket of the original MRGPRX is shallower than the general GPCR, which facilitates the entry of different ligands into the pocket to activate the receptor
.
In addition, their research also found several important sites for ligand binding, which explained well why many ligands of MRGPRX2 are positively charged while the ligands of MRGPRX4 are various negatively charged bile acids
.
Bile acid is an important molecule that causes itching in patients with liver disease and cholestasis
.
The structural studies of their two teams also showed that the downstream of MRGPR can bind to different G proteins, which will guide further signal transduction research in the future
.
In addition, this research to analyze the structure of MRGPR protein also played an important role in drug development research
.
As mentioned above, many clinically used drugs can cause dangerous drug allergic reactions through MRGPRX2
.
After understanding the structure of this receptor, people try to avoid those molecular structures that can bind to the MRGPRX2 ligand binding pocket when developing new drugs, thereby reducing the side effects of the drug
.
In addition, these two papers also make the development of inhibitors of MRGPR more targeted
.
In addition to itching, MRGPR also plays a deductive role in many diseases (such as pain, inflammation, skin diseases, etc.
)
.
It is hoped that in the near future, MRGPRS can be inhibited to treat diseases and benefit mankind
.
Cover image source: 123RF Reference material: [1] Yang, F.
, Guo, L.
, Li, Y.
et al.
Structure, function and pharmacology of human itch receptor complexes.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-04077-y[2] Cao, C.
, Kang, HJ, Singh, I.
et al.
Structure, function and pharmacology of human itch GPCRs.
Nature (2021).
https://doi .
org/10.
1038/s41586-021-04126-6[3] Researchers reveal structure of itch receptors on cells.
Retrieved Nov 17th, 2021 from https://
.
However, with the deepening of research, people gradually realized that the generation of itch is more complicated and unique than previously thought
.
In 2009, the team of Professor Xinzhong Dong of Johns Hopkins University in the United States discovered that a G-coupled protein receptor (GPCR) can produce itch sensation under the stimulation of specific compounds.
This discovery opened up the itch receptor (MRGPR).
) New research field
.
This receptor was later named MRGPRX1 in the human body, unveiling the tip of the iceberg of the itch receptor family
.
After recent years of research, the itch receptor family has gradually expanded
.
From MRGPRA to MRGPRH, plus MRGPRX, a total of 9 itch receptor subfamilies were discovered, which contained more than 50 different receptors
.
For example, in the MRGPRX subfamily, there are four receptors from MRGPRX1 to MRGPRX4
.
Facing the huge and complex family of itch receptors, scientists are working hard to uncover the structural and functional information contained in them
.
This week, two papers published in Nature magazine used cryo-electron microscopy to reveal the fine three-dimensional structure of different itch receptors when combined with ligands
.
One of the papers was completed by the team of Professor Jinpeng Sun and Professor Ning Gao of Peking University.
This research focused on MRGPRX2 in the MRGPR family
.
Professor Sun Jinpeng said that his laboratory is most interested in MRGPRX2.
One reason is that many people in the laboratory have allergic reactions, including pollen allergies
.
Previous studies have found that MRGPRX2, which is mainly distributed in mast cells, can sense a variety of secretins including polycationic compounds and short peptides, causing pseudo-allergic reactions
.
How does MRGPRX2 recognize polycationic compounds and short peptides? This research gives the answer
.
It has been discovered that a variety of positively charged basic small molecules can activate MRGPRX2
.
This study resolved the structure of the complex of MRGPRX2 and Gi trimer when these small molecules act
.
It was found that the two acidic amino acids in the binding pocket of MRGPRX2 can recognize the positively charged basic groups on small molecules and thus bind to small molecules
.
In addition, the research team also found a universal sequence of short peptides that can be recognized by MRGPRX2.
Endogenous short peptides and short peptide drugs containing this sequence can activate MRGPRX2 and cause itching
.
▲Under cryo-electron microscopy, the structure formed by the combination of MRGPRX2 and ligand (picture source: Reference [1]) Scientists have noticed clinically that certain drugs will also activate the MRGPRX2 receptor, triggering the release of histamine, which induces itching Side effects
.
The discovery of this short peptide universal sequence provides an important theoretical basis for the development of drugs that can avoid this side effect
.
In addition, this study also revealed the unique activation mechanism of MRGPRX2, expanding people's understanding of the activation mechanism of the itch receptor family
.
In another paper published at the same time, researchers from the University of North Carolina at Chapel Hill and the University of California, San Francisco also used cryo-electron microscopy to analyze the molecular structure of MRGPRX2 and screened out a highly effective antagonist that can inhibit the activation of MRGPRX2
.
In addition, this study also analyzed in detail MRGPRX4, another member of the itch receptor family
.
MRGPRX4 is located on neurons that sense itching.
Previous studies have found that when this receptor is activated, it can cause pruritus in patients with liver disease cholestasis
.
▲Schematic diagram of polypeptide activation of MRGPRX2 [Image source: UNC SCHOOL OF MEDICINE (ROTH/FAY)] Why belong to the same subfamily, but MRGPRX4 cannot recognize positively charged molecules like MRGPRX2, but binds to negatively charged cholic acid? This study analyzed the structure of MRGPRX4 and found that the two acidic amino acids in MRGPRX2 were blocked by the extracellular part of the receptor, so they could not recognize positively charged molecules in MRGPRX4; on the contrary, the sequence change made the binding pocket carry Positive electricity, which also explains the itching caused by cholestasis
.
These two major studies let us see the true face of itch receptors for the first time, and laid a solid foundation for more basic research and drug development on itch
.
I believe that with more follow-up research, more mysteries about the mysterious perception of tickle will eventually be revealed
.
Experts commented on Dong Xinzhong (Johns Hopkins University, Professor of Neuroscience) Itching is a sensation that everyone can feel every day but is not very clear
.
So how exactly does itching come about? It turns out that some itch receptors in the sensory nerve endings in the skin can detect irritants on the skin that cause itching
.
In addition, some immune cells in the skin, such as mast cells, can also activate and release histamine through other itch receptors to cause itching
.
Twenty years ago, when I was a postdoctoral fellow in the laboratory of Professor David Anderson at the California Institute of Technology, I discovered a new group of G-coupled protein receptor (GPCR) subfamily.
We named it MRGPR (including 50 mouse Mrgprs).
And 8 human MRGPRs)
.
At first, we did not know what the function of MRGPRs is.
After more than ten years of joint efforts in our laboratory and other teams, we discovered that some MRGPRS are the aforementioned itch receptors on sensory nerves and mast cells.
Among them are MRGPRX2 and MRGPRX4
.
The two papers to be reviewed today are the results of research on the analysis of the three-dimensional protein structure of MRGPRX2 and MRGPRX4, which were published simultaneously in the journal Nature
.
One was completed by Sun Jinpeng's team and Peking University Gao Ning's team, and the other was completed by Bryan Roth's team from the University of North Carolina at Chapel Hill and researchers from the University of California, San Francisco
.
Analyzing the structure of MRGPRX is challenging because the protein sequence of this GPCR is very short, most of which are hidden in the cell membrane, so it is impossible to analyze the structure by protein crystallization
.
Professor Sun Jinpeng and Professor Roth are GPCR pharmacologists and cryo-electron microscopy experts.
Their two teams used this technology to analyze the high-resolution protein structures of itch receptors MRGPRX2 and MRGPRX4
.
This is the first time I have seen the appearance of itch receptors in 20 years, so I am very happy
.
The publication of these two papers is also an important milestone in the field of MRGPR research
.
MRGPRs are not the same as the familiar GPCRs
.
Most GPCRs are activated by one or two very specific ligands; while one MRGPR can be activated by many different low-affinity ligands, including small molecule compounds and short peptides
.
The best example is MRGPRX2 on mast cells
.
We found that MRGPRX2 can be activated by dozens of small molecule drugs used clinically and short peptides in the body
.
These drugs can cause mast cells to release histamine and other mediators through MRGPRX2, causing drug allergy symptoms including difficulty breathing, decreased body temperature, redness, and itching
.
So why can so many substances activate MRGPRX2? The results of these two studies perfectly explain this problem that has puzzled us for many years
.
From the protein structure, it can be clearly seen that the ligand binding pocket of the original MRGPRX is shallower than the general GPCR, which facilitates the entry of different ligands into the pocket to activate the receptor
.
In addition, their research also found several important sites for ligand binding, which explained well why many ligands of MRGPRX2 are positively charged while the ligands of MRGPRX4 are various negatively charged bile acids
.
Bile acid is an important molecule that causes itching in patients with liver disease and cholestasis
.
The structural studies of their two teams also showed that the downstream of MRGPR can bind to different G proteins, which will guide further signal transduction research in the future
.
In addition, this research to analyze the structure of MRGPR protein also played an important role in drug development research
.
As mentioned above, many clinically used drugs can cause dangerous drug allergic reactions through MRGPRX2
.
After understanding the structure of this receptor, people try to avoid those molecular structures that can bind to the MRGPRX2 ligand binding pocket when developing new drugs, thereby reducing the side effects of the drug
.
In addition, these two papers also make the development of inhibitors of MRGPR more targeted
.
In addition to itching, MRGPR also plays a deductive role in many diseases (such as pain, inflammation, skin diseases, etc.
)
.
It is hoped that in the near future, MRGPRS can be inhibited to treat diseases and benefit mankind
.
Cover image source: 123RF Reference material: [1] Yang, F.
, Guo, L.
, Li, Y.
et al.
Structure, function and pharmacology of human itch receptor complexes.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-04077-y[2] Cao, C.
, Kang, HJ, Singh, I.
et al.
Structure, function and pharmacology of human itch GPCRs.
Nature (2021).
https://doi .
org/10.
1038/s41586-021-04126-6[3] Researchers reveal structure of itch receptors on cells.
Retrieved Nov 17th, 2021 from https://
