Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 33, Pages 13742-13747Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0907054106
Keywords
cardiac glycosides; crystallography
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Danish Medical Research Council
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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 angstrom resolution in a state analogous to E2 center dot 2K(+)center dot 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.
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