DATE2024.11.07 #Press Releases

Elucidating the mechanism of drug selection for A₃ receptors involved in tumor, inflammation and neural activity.

Summary

A research group led by Professor Osamu Nureki at the School of Science, The University of Tokyo, and Professor Fan-Yan Wei at the Institute of Development, Aging and Cancer, Tohoku University, has characterized the three-dimensional structure of the signaling complex between the adenosine A₃ receptor and the trimeric G protein G_i activated by adenosine or its modifications by cryo-EM (cryo-EEM)-EM)  and single particle analysis.

A₃ receptors are abundant in cancer cells and immune cells and are attracting attention as new drug targets. In particular, a modified adenosine, m⁶A, was known to selectively activate A₃ receptors among adenosine receptors, but the detailed mechanism was not known. In this study, we determined the complex structure of the A₃ receptor bound to m⁶A and the trimeric G protein G_i, and newly discovered that the modified adenosine i⁶A selectively activates the A₃ receptor. They also found that the A₃ receptor has a hydrophobic pocket that is not found in other receptors, and that selective drugs exert their effects by binding to this pocket.

These results are expected to lead to the development of new drugs targeting the A₃ receptor and contribute to the treatment of cancer and inflammation.

Overall structure of A₃R-G_i complex

Links：Tohoku University, Institute of Development, Aging and Cancer, Tohoku University. （in Japanese）

Journals

Journal	Nature Communications
Title of paper	Structural insights into the agonist selectivity of the adenosine A3 receptor