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

Mengmeng Wang; Jing-Xiang Wu; Lei Chen

doi:10.3389/fphar.2022.929684

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

Front Pharmacol. 2022 Jun 30:13:929684. doi: 10.3389/fphar.2022.929684. eCollection 2022.

Authors

Mengmeng Wang^{1

2

3

4}, Jing-Xiang Wu^{1

4}, Lei Chen^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing, China.
² Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
³ Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁴ National Biomedical Imaging Center, Peking University, Beijing, China.

Abstract

Mitiglinide is a highly selective fast-acting anti-diabetic drug that induces insulin secretion by inhibiting pancreatic K_ATP channels. However, how mitiglinide binds K_ATP 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.

Keywords: ABC transporter; KATP; SUR1; diabetes; insulin secretagogues; mitiglinide.