Identification of a Functionally Important Negatively Charged Residue Within the Second Catalytic Site of the SUR1 Nucleotide-Binding Domains

  1. Jeff D. Campbell12,
  2. Peter Proks1,
  3. Jonathan D. Lippiat1,
  4. Mark S.P. Sansom2 and
  5. Frances M. Ashcroft1
  1. 1University Laboratory of Physiology, University of Oxford, Oxford, U.K
  2. 2Laboratory of Molecular Biophysics, University of Oxford, Oxford, U.K
  1. Address correspondence and reprint requests to Prof. Frances M. Ashcroft, University Laboratory of Physiology, University of Oxford, Parks Rd., Oxford, OX1 3PT, U.K. E-mail: frances.ashcroft{at}


The ATP-sensitive K+ channel (KATP channel) couples glucose metabolism to insulin secretion in pancreatic β-cells. It is comprised of sulfonylurea receptor (SUR)-1 and Kir6.2 proteins. Binding of Mg nucleotides to the nucleotide-binding domains (NBDs) of SUR1 stimulates channel opening and leads to membrane hyperpolarization and inhibition of insulin secretion. To elucidate the structural basis of this regulation, we constructed a molecular model of the NBDs of SUR1, based on the crystal structures of mammalian proteins that belong to the same family of ATP-binding cassette transporter proteins. This model is a dimer in which there are two nucleotide-binding sites, each of which contains residues from NBD1 as well as from NBD2. It makes the novel prediction that residue D860 in NBD1 helps coordinate Mg nucleotides at site 2. We tested this prediction experimentally and found that, unlike wild-type channels, channels containing the SUR1-D860A mutation were not activated by MgADP in either the presence or absence of MgATP. Our model should be useful for designing experiments aimed at elucidating the relationship between the structure and function of the KATP channel.


  • 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 25, 2004.
    • Received March 12, 2004.
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