title: Crystal structure of the sodium-potassium pump (Na+,K+-ATPase) with bound potassium and ouabain.
abstract: The sodium-potassium pump (Na(+),K(+)-ATPase) is responsible for establishing Na(+) and K(+) concentration gradients across the plasma membrane and therefore plays an essential role in, for instance, generating action potentials. Cardiac glycosides, prescribed for congestive heart failure for more than 2 centuries, are efficient inhibitors of this ATPase. Here we describe a crystal structure of Na(+),K(+)-ATPase with bound ouabain, a representative cardiac glycoside, at 2.8 A resolution in a state analogous to E2.2K(+).Pi. Ouabain is deeply inserted into the transmembrane domain with the lactone ring very close to the bound K(+), in marked contrast to previous models. Due to antagonism between ouabain and K(+), the structure represents a low-affinity ouabain-bound state. Yet, most of the mutagenesis data obtained with the high-affinity state are readily explained by the present crystal structure, indicating that the binding site for ouabain is essentially the same. According to a homology model for the high affinity state, it is a closure of the binding cavity that confers a high affinity.
authors: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Haruo
authors: H
authors: Ogawa
authors: Takehiro
authors: T
authors: Shinoda
authors: Flemming
authors: F
authors: Cornelius
authors: Chikashi
authors: C
authors: Toyoshima
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D006860:Hydrogen Bonding; D007700:Kinetics; D007783:Lactones / Q000737:chemistry; D008051:Lipid Bilayers; D008968:Molecular Conformation; D016296:Mutagenesis; D010042:Ouabain / Q000737:chemistry*; D011188:Potassium / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry*
chemical_list: D002241:Carbohydrates; D007783:Lactones; D008051:Lipid Bilayers; D010042:Ouabain; D000251:Adenosine Triphosphatases; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium