Toward Linking Structure With Function in ATP-Sensitive K+ Channels

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. suppl 3; pp. S104 - S112
• Main Authors: Bryan, Joseph, Vila-Carriles, Wanda H., Zhao, Guiling, Babenko, Audrey P., Aguilar-Bryan, Lydia
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-12-2004
• Subjects: Adenosine Triphosphate - physiology; Animals; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Homeostasis; Humans; Hypoglycemia; Hypoglycemic Agents - pharmacology; Insulin; Medical sciences; Metabolism; Models, Molecular; Mutation; Potassium Channels - chemistry; Potassium Channels - drug effects; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying - chemistry; Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Inwardly Rectifying - physiology; Protein Conformation; Endocrinopathy; ATP; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.suppl_3.S104

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 (KATP channels) (KIR6.0/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 alpha-helices found in SURs, binds to and activates KIR6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the KIR6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH2-terminus of the KIR. Homology modeling of the SUR1 core offers the possibility of defining the glibenclamide/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 KIR NH2-terminus.