Comparative molecular dynamics simulations of mitogen-activated protein kinase-activated protein kinase 5

Int J Mol Sci. 2014 Mar 19;15(3):4878-902. doi: 10.3390/ijms15034878.

Abstract

The mitogen-activated protein kinase-activated protein kinase MK5 is a substrate of the mitogen-activated protein kinases p38, ERK3 and ERK4. Cell culture and animal studies have demonstrated that MK5 is involved in tumour suppression and promotion, embryogenesis, anxiety, cell motility and cell cycle regulation. In the present study, homology models of MK5 were used for molecular dynamics (MD) simulations of: (1) MK5 alone; (2) MK5 in complex with an inhibitor; and (3) MK5 in complex with the interaction partner p38α. The calculations showed that the inhibitor occupied the active site and disrupted the intramolecular network of amino acids. However, intramolecular interactions consistent with an inactive protein kinase fold were not formed. MD with p38α showed that not only the p38 docking region, but also amino acids in the activation segment, αH helix, P-loop, regulatory phosphorylation region and the C-terminal of MK5 may be involved in forming a very stable MK5-p38α complex, and that p38α binding decreases the residual fluctuation of the MK5 model. Electrostatic Potential Surface (EPS) calculations of MK5 and p38α showed that electrostatic interactions are important for recognition and binding.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitogen-Activated Protein Kinase 14 / chemistry
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / chemistry
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary*
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism
  • Static Electricity
  • Substrate Specificity
  • Thermodynamics

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • MAP-kinase-activated kinase 5
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 14
  • Mitogen-Activated Protein Kinase Kinases