Recently, researchers from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Nan Fajun and Xie Xin, have discovered through research that the 88th histidine in mouse-derived TGR5 (the 89th tyrosine in human-derived TGR5) is responsible for the activity of human and mouse receptors.
The bile acid receptor TGR5 plays an important role in blood glucose homeostasis, energy expenditure and liver protection.
In order to solve this problem, the researchers started from the differences of TGR5 species and compared the TGR5 sequences of different species, focusing on the same amino acids on the human and canine receptors, but different positions on the mouse receptor.
Next, after the researchers mutated the histidine at this position to the tyrosine in the human/canine receptor, the activity of various compounds, especially betulinic acid derivatives, on the mTGR5H88Y mutant was significantly improved, and The difference in activity on hTGR5 is greatly reduced
At the same time, the researchers took the betulinic acid TGR5 agonist XYT528B as a starting point, and optimized the structure of the C3, C17, and C20 positions to obtain the most active compound 11d, which has a nearly higher activity on hTGR5 than INT777.
This study clarified that histidine at position 88 in mouse TGR5 (tyrosine at position 89 in human TGR5) is the key site that causes differences in the activity of TGR5, and the corresponding group at position 88 of mTGR5 was converted through CRISPR/Cas9.
Ying Ying, a doctoral student from Shanghai Institute of Materia Medica, postdoctoral fellow Zhang Chenlu, and Guo Shimeng, a doctoral student jointly trained by Nanjing University of Traditional Chinese Medicine and Shanghai Institute of Materia Medica, are the co-first authors of the paper
Chinese Academy of Sciences Related paper information: https://doi.
https://doi.
org/10.
1021/acs.
jmedchem.
1c00851
This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only.
This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of
the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed
description of the concern or complaint, to
service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content
will be removed immediately.
