Modulatory and catalytic modes of ATP binding by the calcium pump

EMBO J. 2006 Jun 7;25(11):2305-14. doi: 10.1038/sj.emboj.7601135. Epub 2006 May 18.


We present crystal structures of the calcium-free E2 state of the sarcoplasmic reticulum Ca2+ -ATPase, stabilized by the inhibitor thapsigargin and the ATP analog AMPPCP. The structures allow us to describe the ATP binding site in a modulatory mode uncoupled from the Asp351 phosphorylation site. The Glu439 side chain interacts with AMPPCP via an Mg2+ ion in accordance with previous Fe2+ -cleavage studies implicating this residue in the ATPase cycle and in magnesium binding. Functional data on Ca2+ mediated activation indicate that the crystallized state represents an initial stage of ATP modulated deprotonation of E2, preceding the binding of Ca2+ ions in the membrane from the cytoplasmic side. We propose a mechanism of Ca2+ activation of phosphorylation leading directly from the compact E2-ATP form to the Ca2E1-ATP state. In addition, a role of Glu439 in ATP modulation of other steps of the functional cycle is suggested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Calcium-Transporting ATPases / chemistry*
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism*
  • Crystallography, X-Ray
  • Enzyme Activation
  • Magnesium / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Tertiary*
  • Protons
  • Rabbits
  • Thapsigargin / metabolism


  • Protons
  • 5'-adenylyl (beta,gamma-methylene)diphosphonate
  • Thapsigargin
  • Adenosine Triphosphate
  • Calcium-Transporting ATPases
  • Magnesium
  • Calcium