AUTHOR=Wang Mengmeng , Wu Jing-Xiang , Chen Lei 

TITLE=Structural Insights Into the High Selectivity of the Anti-Diabetic Drug Mitiglinide

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.929684

DOI=10.3389/fphar.2022.929684

ISSN=1663-9812

ABSTRACT=<p>Mitiglinide is a highly selective fast-acting anti-diabetic drug that induces insulin secretion by inhibiting pancreatic K<sub>ATP</sub> channels. However, how mitiglinide binds K<sub>ATP</sub> channels remains unknown. Here, we show the cryo-EM structure of the SUR1 subunit complexed with mitiglinide. The structure reveals that mitiglinide binds inside the common insulin secretagogue-binding site of SUR1, which is surrounded by TM7, TM8, TM16, and TM17. Mitiglinide locks SUR1 in the NBD-separated inward-facing conformation. The detailed structural analysis of the mitiglinide-binding site uncovers the molecular basis of its high selectivity.</p>