PKR-inhibitor binds efficiently with human microtubule affinity-regulating kinase 4

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• MAP/microtubule affinity-regulating kinase 4 (MARK4) is implicated in various diseases, including cancer, obesity, diabetes, and neurodegeneration.
• Understanding MARK4's interaction with inhibitors is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of MARK4's N-terminal 59 residues in the binding of PKR-inhibitor.
• To characterize the binding affinity and mechanism of PKR-inhibitor to MARK4 variants.

Main Methods:

• Molecular docking to predict binding interactions.
• Molecular dynamics (MD) simulations to assess complex stability.
• Fluorescence-binding studies to determine binding affinity and site number.

Main Results:

• PKR-inhibitor binds to the kinase domain of MARK4 via hydrophobic and hydrogen bonds.
• MD simulations showed stable complexes for both MARK4 variants with the inhibitor.
• Fluorescence data revealed high binding affinity, with no significant difference between MARK4 variants, indicating the N-terminus is not critical for binding.

Conclusions:

• The 59 N-terminal residues of MARK4 do not play a crucial role in PKR-inhibitor binding.
• These findings provide insights for designing novel, selective PKR-inhibitor derivatives as therapeutic agents for MARK4-associated diseases.