title: How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent.
abstract: 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.
authors.affiliation: Faculty of Chemistry and Pharmacy, Sofia University, Sofia 1164, Bulgaria.
authors.forename: Todor
authors.initials: T
authors.lastname: Dudev
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Cédric
authors.initials: C
authors.lastname: Grauffel
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.|Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D002412:Cations; D008094:Lithium / Q000378:metabolism* / Q000627:therapeutic use*; D008274:Magnesium / Q000378:metabolism*; D008968:Molecular Conformation; D012996:Solutions; D013816:Thermodynamics
chemical_list: D002412:Cations; D012996:Solutions; D000255:Adenosine Triphosphate; D008094:Lithium; D008274:Magnesium