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

Journal of Chemical Theory and Computation
Todor DudevCarmay Lim

Abstract

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 d...Continue Reading

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Citations

Apr 6, 2021·Journal of Chemical Theory and Computation·Cédric GrauffelCarmay Lim
Nov 13, 2019·Journal of Chemical Theory and Computation·Cédric GrauffelCarmay Lim
Nov 10, 2018·Inorganic Chemistry·Todor DudevCarmay Lim
Sep 27, 2019·Accounts of Chemical Research·Todor DudevCarmay Lim
Sep 14, 2021·The Journal of Physical Chemistry. B·Todor DudevCarmay Lim

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