Nature: Heavyweight! Scientists observe the entire process of serotonin activating receptors

Serotonin (3A) receptors are common drug targets in various disease therapies, including pain, gastrointestinal disorders, and psychological disorders. However, researchers currently do not have a clear understanding of the three-dimensional structure of serotonin receptors. Clarifying the structure of serotonin receptors may provide clues for researchers to design drugs with lower side effects; Recently, an article was published in a magazineNatureIn a research report, scientists from Case Western Reserve University used a high-performance microscope to observe the entire process of serotonin activating its receptors, revealing molecular details of serotonin receptors that could improve drug development for treating various human diseases.

Image source: Case Western Reserve University School of Medicine

Serotonin receptors are located on the cell membranes of various tissues in the body, including the brain, stomach, and surrounding nervous system; Drugs that inhibit serotonin receptors can help control postoperative nausea in patients, promote cancer therapy, and can also be used to treat gastrointestinal disorders such as irritable bowel syndrome. These inhibitors can also be used as antidepressants to promote individual attention and memory.

Researcher Professor Sudha Chakrapani said that the widespread use of drugs often brings some side effects, partly due to poor interactions between drug receptors, which often limits the progress of researchers in designing successful and safe therapies. Currently, researchers are limited in understanding the structure of serotonin receptors, and they are not clear about what processes occur after serotonin binds to their background; In this study, researchers elucidated the mechanism and process of serotonin activating systemic serotonin receptors at a level close to a single atom.

Using advanced microscopy techniques that have won the Nobel Prize, researchers have studied the mechanism of the interaction between serotonin and its receptors. Imaging results show that serotonin can bind to its receptors and twist open the channels of action, which can promote the entry of molecules into the cell interior; Subsequently, the researchers used simulation methods to observe how sodium molecules pass through newly opened channels. In the article, the researchers emphasized the different conformations of serotonin receptors, which may lead to some permeability of cells to certain molecules, which is crucial for the development of new drugs; The special part of the receptor is also important for proper channel function.

The entire serotonin receptor occurs in a space approximately one billionth of a meter wide, and researchers have only recently captured this tiny molecule using a microscope. In this study, researchers used cryo electron microscopy technology, which won the Nobel Prize in Chemistry in 2017, to capture protein activity using high-energy microscopy and compile it into a three-dimensional structural model. In the past few years, this new microscopy technology has been able to help researchers observe protein structures related to other diseases such as kidney stones. Last year, researcher Chakrapani used cryo electron microscopy technology to observe serotonin receptors, which provided some clues for this study.

The researchers hope that the results of this study can help develop more drugs to target specific regions or functions of serotonin receptors; Dr. Sandip Basak, a later researcher, said that it seems that new or different drugs can act as effective serotonin inhibitors, especially those designed to be more effective than current drugs. In the future, we will continue to conduct in-depth research and design more safe therapies to regulate serotonin receptors and treat a range of human diseases. (Biological Valley)

Original source:

Sandip Basak, Yvonne Gicheru, Shanlin Rao, et al. Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor.Nature, 2018; DOI: 10.1038/s41586-018-0660-7