The effect of Li+ on GSK-3 inhibition: Molecular dynamics simulation

Abstract

Glycogen synthase kinase-3 (GSK-3) is a kind of serine-threonine protein kinase. It places important roles in several signaling pathways and it is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimer's disease and chronic inflammation. Mg(2+) ions which interact with ATP are conserved in GSK. They are important in phosphoryl transfer. Li(+) is an inhibitor for GSK-3. It is used to treat bipolar mood disorder. This paper illustrates the effect of Li(+) on GSK-3. When Mg(I)(2+) is replaced by Li(+), the atom fluctuation of GSK-3 will rise, and the in-line phosphoryl transfer mechanism is probably demolished and the binding of pre-phosphorylated substrates may be disturbed. All the results we obtained clearly suggest that inhibition to GSK-3 is caused by the Mg(I)(2+) replacement with Li(+).

Molecular framework for response to imatinib mesylate in systemic sclerosis

“…Experimental evidences and computational studies for the appropriate orientation and conformation of ATP triphosphate moiety, crucial for the phosphoryl‐transfer reaction between ATP and the serine hydroxyl group on the substrate, have been well‐established 48–52. In analogy to our previous studies of GSK3β/ATP and GSK3β/ATP/substrate complexes,16, 21, 23 we also corroborated, by virtue of MD simulations, that the disruption of the in‐line phosphoryl transfer of ATP may inhibit the enzymatic activity. Therefore, the dihedral angle, O α3 ‐P β ‐O β3 ‐P γ [see Fig.…”

“…Since deregulation of GSK3β has been closely related with a wide range of human pathological conditions, it has made GSK3β the focus of intense interest as a potential therapeutic target. The central role of GSK3β in biology has stimulated colossal efforts to elucidate the relationship between structure and functions of GSK3β in recent years 14–26…”

“…Experimentally, Raves and Harwood observed that Li + is a competitive inhibitor with regard to only one of the two Mg 2+ ions (one is Li + ‐sensitive and the other is Li + ‐insensitive) 29. Recent quantum mechanical/molecular mechanical (QM/MM) studies and molecular dynamics (MD) simulations have corroborated that Li + is sufficient for inhibiting the GSK3β activity by dislodging of the Mg 2+ ‐1 ion from the metal binding site 16, 21. Furthermore, due to the weak interactions of other group I metal ions (Na + , K + , and Rb + ) with ATP, the three metal ions depart from the Mg 2+ ‐1 binding site.…”

Wogonin influences vascular permeability via Wnt/β-catenin pathway

“…To confirm wogonin affected β‐catenin through modulation of destruction complex, a well known GSK‐3β inhibitor, LiCl was used. LiCl can inhibit GSK‐3β by acting as a competitive inhibitor of Mg 2+ inducing Ser 9 autophosphorylation . The results revealed LiCl recovered the accumulation of β‐catenin suppressed by wogonin in HUVECs.…”

How calcium inhibits the magnesium‐dependent kinase gsk3β: A molecular simulation study

“…Mg 21 and Ca 21 , the most versatile metal cofactors in cellular biochemistry, are frequently associated with catalytic or regulatory activities of many metalloproteins. [1][2][3][4] In many cases, Mg 21 and Ca 21 can stabilize the structure of the folded protein, function as a Lewis acid to activate the reacting species, and perform in the electrostatic stabilization of intermediates and transition states. 5-8 The two metal ions share similar characteristics: both of them are stable in the 12 oxidation states, are redox-inert and prefer hard donors, with oxygen being the most preferred coordination atom.…”