The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels

ATP-sensitive potassium channels (K_ATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, K_ATP inhibitors have been prescribed for diabetes and K_ATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus K_ATP channel activity. SIGNIFICANCE STATEMENT: ATP-sensitive potassium channels (K_ATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. K_ATP channels are important drug targets. Both K_ATP inhibitors (insulin secretagogues) and K_ATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of K_ATP structural pharmacology.