Open AccessCrystal structure of the sodium-potassium pump (Na + ,K + -ATPase) with bound potassium and ouabain
Author(s) -
Hirotaka Ogawa,
Takehiro Shinoda,
Flemming Cornelius,
Chikashi Toyoshima
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0907054106
Subject(s) - ouabain , chemistry , sodium pump , potassium , cardiac glycoside , crystallography , binding site , crystal structure , sodium , stereochemistry , atpase , biochemistry , enzyme , organic chemistry
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 Å 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.