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.