Dr. Lim, Carmay ’s Lab林小喬 博士 實驗室

How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent

Adenosine triphosphate (ATP), the major energy currency of the cell, exists in solution mostly as ATP-Mg. Recent experiments suggest that Mg²⁺ interacts with the highly charged ATP triphosphate group and Li⁺ can co-bind with the native Mg²⁺ to form ATP-Mg-Li and modulate the neuronal purine receptor response. However, it is unclear how the negatively charged ATP triphosphate group binds Mg²⁺ and Li⁺ (i.e. which phosphate group(s) bind Mg²⁺/Li⁺) and how the ATP solution conformation depends on the type of metal cation and the metal-binding mode. Here, we reveal the preferred ATP-binding mode of Mg²⁺/Li⁺ alone and combined: Mg²⁺ prefers to bind ATP tridentately to each of the three phosphate groups, but Li⁺ prefers to bind bidentately to the terminal two phosphates. We show that the solution ATP conformation depends on the cation and its binding site/mode, but it does not change significantly when Li⁺ binds to Mg²⁺-loaded ATP. Hence, ATP-Mg-Li, like Mg²⁺-ATP, can fit in the ATP-binding site of the host enzyme/receptor, activating specific signaling pathways.