-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
▎Editor of WuXi AppTec's content team The top academic journal "Cell" recently published an online research paper jointly by Professor Yifan Cheng and Professor David Julius, a well-known scientist from the University of California, San Francisco (UCSF)
.
Using advanced single-particle cryo-electron microscopy (cryo-EM) technology, scientists analyzed a series of conformational transitions of the capsaicin receptor TRPV1, revealing the mechanism by which different analgesics activate TRPV1
.
TRPV1 is an important protein that allows us to perceive pain
.
It was first discovered in 1997 by Professor David Julius, the co-corresponding author of this study .
As an ion channel protein, TRPV1 is expressed in large amounts on sensory neurons.
When activated, it allows calcium ions to pass through this channel, thereby allowing nerve cells to send out electrical signals
.
Although TRPV1 is called the capsaicin receptor, in addition to being activated by capsaicin (so hot peppers can cause pain), Professor Julius and colleagues discovered that the toxin DkTx produced by poisonous spiders, and the gum lipotoxin produced by plants Compounds that induce pain and inflammation, such as RTX, also activate TRPV1
.
In addition, TRPV1 is also sensitive to high temperatures and will be activated by temperatures above 43 degrees Celsius
.
Because of these connections, TRPV1 has become a potential analgesic target, attracting the attention of drug developers
.
▲Professor David Julius won the 2020 "Scientific Breakthrough Award" for discovering molecules, cells and mechanisms related to pain perception (picture source: reference [3]) In 2013, structural biologist Professor Cheng Yifan and Professor David Julius collaborated in "Nature" published a paper, showing the cryo-EM structure of TRPV1 for the first time with an atomic resolution of 3.
4 angstroms, and seeing that different parts of the TRPV1 channel can change conformation in response to different molecules, thus setting off the field of structural biology.
The cryo-electron microscopy revolution"
.
In this study, the two scientists collaborated in-depth and demonstrated the diversity, uniqueness and commonality of TRPV1 activation pathways under the action of different ligands, providing more targeted guidance for the development of drugs targeting TRPV1
.
▲Co-corresponding author Professor Yifan Cheng and his postdoctoral fellow and the first author Dr.
Kaihua Zhang (picture source: UCSF laboratory homepage) After joining the team, the first author Dr.
Kaihua Zhang applied single-particle cryo-electron microscopy technology to optimize sample preparation conditions and data The processing parameters have successfully taken a "snapshot" of a series of intermediate structural states when TRPV1 binds to different ligands, which strongly explains how TRPV1 can selectively let cations of different sizes pass through dynamic changes
.
For example, these structures show how the spider toxin DkTx couples and triggers the opening of the lower gate of TRPV1
.
Phytotoxin RTX directly regulates the opening of TRPV1 through competition with endogenous phosphatidylinositol (PI) molecules, and will cause conformational changes of the subunits when occupying the four subunits of TRPV1 one by one
.
In addition, the researchers also directly observed that under acidic conditions, protons gradually affect the conformation of TRPV1 and promote the process of channel opening
.
▲ Schematic diagram of this study (picture source: Reference [1]) Taken together, these findings reveal the mechanism of conformational changes related to key regulatory sites, which will not only provide new ideas for drug development targeting TRPV1, but will also help more Deeply understand the function of TRP family ion channels and even other signaling proteins
.
Source of title picture: 123RF Reference: [1] Kaihua Zhang et al.
, (2021) Structural snapshots of TRPV1 reveal mechanism of polymodal functionality.
Cell.
Doi: https://doi.
org/10.
1016/j.
cell.
2021.
08.
012[2] Maofu Liao et al.
, (2021) Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
Nature.
Doi: https://doi.
org/10.
1038/nature12822[3] https://www.
ucsf.
edu/news/2019/09/415336/david-julius-receives-breakthrough-prize-work-pain-sensation
.
Using advanced single-particle cryo-electron microscopy (cryo-EM) technology, scientists analyzed a series of conformational transitions of the capsaicin receptor TRPV1, revealing the mechanism by which different analgesics activate TRPV1
.
TRPV1 is an important protein that allows us to perceive pain
.
It was first discovered in 1997 by Professor David Julius, the co-corresponding author of this study .
As an ion channel protein, TRPV1 is expressed in large amounts on sensory neurons.
When activated, it allows calcium ions to pass through this channel, thereby allowing nerve cells to send out electrical signals
.
Although TRPV1 is called the capsaicin receptor, in addition to being activated by capsaicin (so hot peppers can cause pain), Professor Julius and colleagues discovered that the toxin DkTx produced by poisonous spiders, and the gum lipotoxin produced by plants Compounds that induce pain and inflammation, such as RTX, also activate TRPV1
.
In addition, TRPV1 is also sensitive to high temperatures and will be activated by temperatures above 43 degrees Celsius
.
Because of these connections, TRPV1 has become a potential analgesic target, attracting the attention of drug developers
.
▲Professor David Julius won the 2020 "Scientific Breakthrough Award" for discovering molecules, cells and mechanisms related to pain perception (picture source: reference [3]) In 2013, structural biologist Professor Cheng Yifan and Professor David Julius collaborated in "Nature" published a paper, showing the cryo-EM structure of TRPV1 for the first time with an atomic resolution of 3.
4 angstroms, and seeing that different parts of the TRPV1 channel can change conformation in response to different molecules, thus setting off the field of structural biology.
The cryo-electron microscopy revolution"
.
In this study, the two scientists collaborated in-depth and demonstrated the diversity, uniqueness and commonality of TRPV1 activation pathways under the action of different ligands, providing more targeted guidance for the development of drugs targeting TRPV1
.
▲Co-corresponding author Professor Yifan Cheng and his postdoctoral fellow and the first author Dr.
Kaihua Zhang (picture source: UCSF laboratory homepage) After joining the team, the first author Dr.
Kaihua Zhang applied single-particle cryo-electron microscopy technology to optimize sample preparation conditions and data The processing parameters have successfully taken a "snapshot" of a series of intermediate structural states when TRPV1 binds to different ligands, which strongly explains how TRPV1 can selectively let cations of different sizes pass through dynamic changes
.
For example, these structures show how the spider toxin DkTx couples and triggers the opening of the lower gate of TRPV1
.
Phytotoxin RTX directly regulates the opening of TRPV1 through competition with endogenous phosphatidylinositol (PI) molecules, and will cause conformational changes of the subunits when occupying the four subunits of TRPV1 one by one
.
In addition, the researchers also directly observed that under acidic conditions, protons gradually affect the conformation of TRPV1 and promote the process of channel opening
.
▲ Schematic diagram of this study (picture source: Reference [1]) Taken together, these findings reveal the mechanism of conformational changes related to key regulatory sites, which will not only provide new ideas for drug development targeting TRPV1, but will also help more Deeply understand the function of TRP family ion channels and even other signaling proteins
.
Source of title picture: 123RF Reference: [1] Kaihua Zhang et al.
, (2021) Structural snapshots of TRPV1 reveal mechanism of polymodal functionality.
Cell.
Doi: https://doi.
org/10.
1016/j.
cell.
2021.
08.
012[2] Maofu Liao et al.
, (2021) Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
Nature.
Doi: https://doi.
org/10.
1038/nature12822[3] https://www.
ucsf.
edu/news/2019/09/415336/david-julius-receives-breakthrough-prize-work-pain-sensation
