In:
Chemical Biology & Drug Design, Wiley, Vol. 83, No. 6 ( 2014-06), p. 721-730
Abstract:
Glycogen synthase kinase 3 β ( GSK 3 β ) is a multifunctional serine/threonine protein kinase that is involved in several biological processes including insulin and Wnt signaling pathways. GSK 3 β can be phosphorylated by the protein kinase B ( PKB ). The mutations of A rg4 and A rg6 to alanine at N ‐terminal GSK 3 β have been reported to impair its ability to autophosphorylate at S er9. Despite the extensive experimental observations, the detailed mechanism for the auto‐inhibition of GSK 3 β has not been rationalized at the molecular level. In this study, we have demonstrated the structural consequences of GSK 3 β R 4 A and R 6 A mutations and the atomic changes that influenced the loss of PKB ‐binding affinity. Molecular dynamics simulation results suggested significant loss in atomic contacts in the R 4 A and R 6 A mutant systems compared to the wild‐type system. Furthermore, we observed many notable changes (such as conformation, residues motions, hydrogen bonds, and binding free energy) in the mutated GSK 3 β – PKB complexes. Loss of binding affinity in the mutated systems rendered the decrease in GSK 3 β phosphorylation, which, in turn, impaired the auto‐inhibition of GSK 3 β . The significant outcomes obtained from this study can explain the auto‐inhibition of GSK 3 β and maybe facilitate type 2 diabetes mellitus researches and in developing the potent drug therapies.
Type of Medium:
Online Resource
ISSN:
1747-0277
,
1747-0285
DOI:
10.1111/cbdd.2014.83.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2216600-2
SSG:
12
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