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

  1. Joseph Bryan1,
  2. Wanda H. Vila-Carriles2,
  3. Guiling Zhao1,
  4. Audrey P. Babenko1 and
  5. Lydia Aguilar-Bryan13
  1. 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
  2. 2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas
  3. 3Department of Medicine, Baylor College of Medicine, Houston, Texas
  1. 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

Abstract

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 α-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.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 12, 2004.
    • Received March 13, 2004.
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