Modulatory and catalytic modes of ATP binding by the calcium pump

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Abstract
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.

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