How Native and Non-Native Cations Bind and Modulate the Properties of GTP/ATP

Adenosine triphosphate (ATP) and guanosine triphosphate (GTP) exist in physiological solution mostly bound to cations. Interestingly, their cellular Mg²⁺-bound forms have been shown to bind Li⁺, a first-line drug for bipolar disorder. However, solution structures of NTP/NDP (N = A or G) bound to Li⁺ and/or Mg²⁺ have not been solved, thus precluding knowledge of how the native Mg²⁺-bound cofactor conformation changes upon binding non-native Li⁺ and/or switching its environment from aqueous solution to proteins. Using well-calibrated methods that reproduce experimental structural and thermodynamic parameters of several Mg²⁺/Li⁺-nucleotide complexes, we show that the native NTP/NDP-Mg²⁺ cofactor adopts a "folded" conformation in water that remains unperturbed upon Li⁺ binding. We further show that the ATP-binding pockets of receptors such as P2X are complementary in shape to the "folded" ATP-Mg²⁺ solution structure, whereas the elongated GTP-binding pockets found in G-proteins necessitate the GTP-Mg²⁺ cofactor to undergo a conformational change from its "folded" conformation in solution to an extended one upon G-protein binding. Implications of the findings on how Li⁺, in its bound state, can manifest its therapeutic effects are discussed.