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

Abstract

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.

Harnessing Allostery: A Novel Approach to Drug Discovery

“…The 518 protein kinases encoded in the human genome provide versatile regulatory mechanisms of biological processes, ranging from cell division to proliferation and apoptosis . Upon phosphorylation of residues (Ser, Thr, and Tyr) in the activation loop, protein kinases are transformed into their catalytically competent active state . Despite diversity in its primary amino acid sequence, the overall structure of the kinase catalytic core domain is highly similar, consisting of two lobes, a smaller N‐terminal lobe and a larger C‐terminal lobe, with an ATP binding site located in a deep intervening cleft between the two lobes.…”

“…104,105 Upon phosphorylation of residues (Ser, Thr, and Tyr) in the activation loop, protein kinases are transformed into their catalytically competent active state. [106][107][108] Despite diversity in its primary amino acid sequence, the overall structure of the kinase catalytic core domain is highly similar, consisting of two lobes, a smaller N-terminal lobe and a larger C-terminal lobe, with an ATP binding site located in a deep intervening cleft between the two lobes. This structural feature presents an immense challenge to design selective protein kinase inhibitors that target the conserved ATP binding site for the treatment of numerous pathological conditions.…”

Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

“…Energy minimizations, including steepest descent and conjugate gradient algorithms, were carried out to remove bad contacts in the initial structures using the previously reported protocol [20][21][22]. After relaxation, the two systems were heated from 0 to 300 K in 200 ps, which was followed by constant temperature equilibration at 300 K for 300 ps.…”

Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy

“…58 Furthermore, GSK3B , a HB in our network model (Supplementary Table S6), is a ubiquitous serine/threonine kinase that catalyzes the transfer of γ -phosphate of ATP to the hydroxyl oxygen of the Ser and Thr residues of a kinase-specific protein substrate is a Mg 2+ -dependent kinase. 59 Its aberrant function has been linked to diverse neurological disorders such as AD. 60 Lower concentrations of Mg 2+ were described in children with autism.…”