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Diabetes 53:S104-S112, 2004
© 2004 by the American Diabetes Association, Inc.

Section III: The Beta-Cell ATP-Sensitive K+ Channels

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

Joseph Bryan1, Wanda H. Vila-Carriles2, Guiling Zhao1, Audrey P. Babenko1, and Lydia Aguilar-Bryan1,3

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas
3 Department of Medicine, Baylor College of Medicine, Houston, Texas

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 KIR 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.

Address correspondence and reprint requests to Joseph Bryan, PhD, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. E-mail: jbryan{at}bcm.tmc.edu


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