Structural insights into the high selectivity of the anti-diabetic drug mitiglinide

Mitiglinide is a highly selective fast-acting anti-diabetic drug that inhibits pancreatic KATP channels to induce insulin secretion. However, how mitiglinide binds KATP channels remains unknown. Here, we show the cryo-EM structure of the SUR1 subunit in complex with mitiglinide. The structure reveals that mitiglinide binds inside the common insulin secretagogue-binding site in the transmembrane domain of SUR1, locking SUR1 in a NBD-separated inward-facing conformation. The detailed structural analysis uncovers the molecular basis of the high selectivity of mitiglinide.