Homology modeling and molecular dynamics study of GSK3/SHAGGY-like kinase

Comput Biol Chem. 2004 Jul;28(3):179-88. doi: 10.1016/j.compbiolchem.2004.02.003.

Abstract

Although the GSK3/SHAGGY-like kinase is a highly conserved serine/threonine kinase implicated in many signaling pathways in eukaryotes, the lack of knowledge of its three-dimensional (3D) structure has hindered efforts to understand the binding specificities of substrate and catalytic mechanism. To understand the structure-activity relationships, the protein 3D structure was built by using homology modeling based on the known X-ray diffraction structure of Glycogen synthase kinase-3beta (Gsk3beta) and the model structure was further refined using unrestrained molecular dynamics simulations. The research indicates that the general 3D organization of the GSK3/SHAGGY-like kinase is a typical kinase family and comprises an N-terminal domain of beta-sheet and a larger C-terminal domain mainly constituted by alpha-helix. In order to understand the molecular interactions between the natural substrate-ATP and GSK3/SHAGGY-like kinase, a 3D model of the complex ATP-GSK3/SHAGGY-like kinase is developed by molecular docking program, which is helpful to guide the experimental realization and the new mutant designs as well. One important finding is that the identification of the key binding-site residue of Lys69 which plays an important role in the catalysis of GSK3/SHAGGY-like kinase and this is in consistent with experimental observation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Binding Sites
  • CDC2-CDC28 Kinases / chemistry
  • CDC2-CDC28 Kinases / genetics
  • Computer Simulation*
  • Cyclin-Dependent Kinase 2
  • Glycogen Synthase Kinase 3 / chemistry*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Sequence Data
  • Plant Proteins / chemistry
  • Plant Proteins / genetics
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Static Electricity
  • Structural Homology, Protein*
  • Surface Properties
  • Thermodynamics

Substances

  • Amino Acids
  • Plant Proteins
  • Adenosine Triphosphate
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Glycogen Synthase Kinase 3