Allosteric Regulation of Glycogen Synthase Kinase 3β: A Theoretical Study

Abstract

Glycogen synthase kinase 3β (GSK-3β) is a serine−threonine kinase belonging to the CMGC family that plays a key role in many biological processes, such as glucose metabolism, cell cycle regulation, and proliferation. Like most protein kinases, GSK-3β is regulated via multiple pathways and sites. We performed all-atom molecular dynamics simulations on the unphosphorylated and phosphorylated unbound GSK-3β and the phosphorylated GSK-3β bound to a peptide substrate, its product, and a derived inhibitor. We found that GSK-3β autophosphorylation at residue Tyr216 results in widening of the catalytic groove, thereby facilitating substrate access. In addition, we studied the interactions of the phosphorylated GSK-3β with a substrate and peptide inhibitor located at the active site and observed higher affinity of the inhibitor to the kinase. Furthermore, we detected a potential remote binding site which was previously identified in other kinases. In agreement with experiments we observed that binding of specific peptides at this remote site leads to stabilization of the activation loop located in the active site. We speculate that this stabilization could enhance the catalytic activity of the kinase. We point to this remote site as being structurally conserved and suggest that the allosteric phenomenon observed here may occur in the protein kinase superfamily.

Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors to activate Wnt/β-catenin pathway

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Effect of double mutations K214/A–E215/Q of FRATide on GSK3β: insights from molecular dynamics simulation and normal mode analysis

“…Computational studies are increasingly gaining interest in elucidating the pathways connecting the active and inactive forms of the kinases and play an important complementary role with respect to experiments (Buch et al 2010;Tang et al 2011;Lu et al 2011b, c). Recently, we elucidate the allosteric regulation mechanism regarding mutation K85M of GSK3b on the GSK3b-FRATide complex via molecular dynamics (MD) simulation and normal mode analysis (NMA) (Lu et al 2011d).…”

Molecular framework for response to imatinib mesylate in systemic sclerosis

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