Toward linking structure with function in ATP-sensitive K+ channels

Advances in understanding the overall structural features of inward rectifiers and ATP-binding cassette (ABC) transporters are providing novel insight into the architecture of ATP-sensitive K+ channels (K-ATP channels) (K(IR)6-0/SUR)(4). The structure of the K-IR pore has been modeled on bacterial K+ channels, while the lipid-A exporter, MsbA, provides a template for the MDR-like core of sulfonylurea receptor (SUR)-1. TMD0, an NH2-terminal bundle of five et-helices found in SURs, binds to and activates K(IR)6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the K(IR)6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH2-terminus of the K-IR. Homology modeling of the SUR1 core offers the possibility of defining the gliben-clamide/sulfonylurea binding pocket. Consistent with 30-year-old studies on the pharmacology of hypoglycemic agents, the pocket is bipartite. Elements of the COOH-terminal half of the core recognize a hydrophobic group in glibenclamide, adjacent to the sulfonylurea moiety, to provide selectivity for SUR1, while the benzamido group appears to be in proximity to L0 and the K-IR NH2-terminus.