title: Dissection of the difference between the group I metal ions in inhibiting GSK3β: a computational study.
abstract: Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase that requires two cofactor Mg(2+) ions for catalysis in regulating many important cellular signals. Experimentally, Li(+) is a competitive inhibitor of GSK3β relative to Mg(2+), while this mechanism is not experienced with other group I metal ions. Herein, we use native Mg(2)(2+)-Mg(1)(2+) GSK3β and its Mg(2)(2+)-M(1)(+) (M = Li, Na, K, and Rb) derivatives to investigate the effect of metal ion substitution on the mechanism of inhibition through two-layer ONIOM-based quantum mechanics/molecular mechanics (QM/MM) calculations and molecular dynamics (MD) simulations. The results of ONIOM calculations elucidate that the interaction of Na(+), K(+), and Rb(+) with ATP is weaker compared to that of Mg(2+) and Li(+) with ATP, and the critical triphosphate moiety of ATP undergoes a large conformational change in the Na(+), K(+), and Rb(+) substituted systems. As a result, the three metal ions (Na(+), K(+), and Rb(+)) are not stable and depart from the active site, while Mg(2+) and Li(+) can stabilize in the active site, evident in MD simulations. Comparisons of Mg(2)(2+)-Mg(1)(2+) and Mg(2)(2+)-Li(1)(+) systems reveal that the inline phosphor-transfer of ATP and the two conserved hydrogen bonds between Lys85 and ATP, together with the electrostatic potential at the Li(1)(+) site, are disrupted in the Mg(2)(2+)-Li(1)(+) system. These computational results highlight the possible mechanism why Li(+) inhibits GSK3β.
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China.
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Lu
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Jiang
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zou
authors.forename: Tian-Xing
authors.initials: TX
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006860:Hydrogen Bonding; D008670:Metals / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D008670:Metals; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3