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

Sun, Honglei; Jiang, Yong‐Jun; Q, Yu; Luo, Congcong; Zou, Jian‐Wei

doi:10.1007/s00894-010-0738-0

Cited by 17 publications

(60 citation statements)

References 26 publications

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“…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.…”

Section: Resultsmentioning

confidence: 83%

“…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…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Molecular framework for response to imatinib mesylate in systemic sclerosis

Chung

Fiorentino

BenBarak³

et al. 2009

Arthritis & Rheumatism

113

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Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFR␤ and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10 ؊8 ). The response of these patients and the findings of the analyses suggest that PDGFR␤ and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

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Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular framework for response to imatinib mesylate in systemic sclerosis

Chung

Fiorentino

BenBarak³

et al. 2009

Arthritis & Rheumatism

113

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“…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.…”

Section: Discussionmentioning

confidence: 89%

Wogonin influences vascular permeability via Wnt/β-catenin pathway

Song

Zhou

et al. 2013

Mol. Carcinog.

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Wogonin, a flavone from the root of Scutellaria baicalensis Georgi, has shown various biological activities. In our previous study, it was confirmed that wogonin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) by affecting its stability under hypoxia. However, it is still unknown whether wogonin could influence Wnt/β-catenin pathway under hypoxia. In this study, we found that wogonin disrupted Wnt/β-catenin signaling and reduced the secretion of vascular endothelial growth factor (VEGF, also known as vascular permeability factor, VPF), which increased vascular permeability in certain diseases. It was found that wogonin suppressed HUVECs hyperactivity and actin remodeling induced by hypoxia, inhibited transendothelial cell migration of the human breast carcinoma cell MDA-MB-231 and the extravasated Evans in vivo Miles vascular permeability assay. Wogonin-treated cells showed a decrease in the expression of Wnt protein and its co-receptors, as well as a parallel increase in the expression of Axin and GSK-3β in degradation complex, leading to degradation of β-catenin. In addition, wogonin promoted the binding between Axin and β-catenin, increased ubiquitination of β-catenin and promoted its degradation. Interestingly, wogonin decreased the expression of TCF-1, TCF-3, and LEF-1 and inhibited nuclear accumulation of β-catenin as well as the binding of β-catenin and TCF-1, TCF-3, or LEF-1. All of the above results showed that wogonin could inhibit the expression of VEGF, which is an important factor regulated by β-catenin. Taken together, the results suggested that wogonin was a potent inhibitor of Wnt/β-catenin and influenced vascular permeability, and this might provide new therapeutics in certain diseases.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Huang

et al. 2013

Proteins

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Glycogen synthase kinase 3β (GSK3β) is a ubiquitous serine/threonine kinase that plays a pivotal role in many biological processes. GSK3β catalyzes the transfer of γ-phosphate of ATP to the unique substrate Ser/Thr residues with the assistance of two natural activating cofactors Mg(2+). Interestingly, the biological observation reveals that a non-native Ca(2+) ion can inhibit the GSK3β catalytic activity. Here, the inhibitory mechanism of GSK3β by the displacement of native Mg(2+) at site 1 by Ca(2+) was investigated by means of 80 ns comparative molecular dynamics (MD) simulations of the GSK3β···Mg(2+)-2/ATP/Mg(2+) -1 and GSK3β···Mg(2+)-2/ATP/Ca(2+)-1 systems. MD simulation results revealed that using the AMBER point charge model force field for Mg(2+) was more appropriate in the reproduction of the active site architectural characteristics of GSK3β than using the magnesium-cationic dummy atom model force field. Compared with the native Mg(2+) bound system, the misalignment of the critical triphosphate moiety of ATP, the erroneous coordination environments around the Mg(2+) ion at site 2, and the rupture of the key hydrogen bond between the invariant Lys85 and the ATP O(β2) atom in the Ca(2+) substituted system were observed in the MD simulation due to the Ca(2+) ion in active site in order to achieve its preferred sevenfold coordination geometry, which adequately abolish the enzymatic activity. The obtained results are valuable in understanding the possible mechanism by why Ca(2+) inhibits the GSK3β activity and also provide insights into the mechanism of Ca(2+) inhibition in other structurally related protein kinases.

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

Cited by 17 publications

References 26 publications

Molecular framework for response to imatinib mesylate in systemic sclerosis

Molecular framework for response to imatinib mesylate in systemic sclerosis

Wogonin influences vascular permeability via Wnt/β-catenin pathway

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

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