title: 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 Tyr(216) 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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Institute of Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Buch
authors.forename: Dan
authors.initials: D
authors.lastname: Fishelovitch
authors.forename: Nir
authors.initials: N
authors.lastname: London
authors.forename: Barak
authors.initials: B
authors.lastname: Raveh
authors.forename: Haim J
authors.initials: HJ
authors.lastname: Wolfson
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D008024:Ligands; D010455:Peptides; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3