title: Dynamical insights of Mnk2 kinase activation by phosphorylation to facilitate inhibitor discovery.
abstract: OBJECTIVE
  Mitogen-activated protein kinase-interacting kinases (Mnks) are emerging anticancer targets. Mnks feature unique structural features, enhancing their importance for selective inhibitor discovery. Nonetheless, the lack of structural details obstruct the development of selective Mnk inhibitors.
  
  
  RESULTS
  We disclose the first complete structure model of the activated state of Mnk2. Using all-atom accelerated molecular dynamics, we also demonstrate that its activation by phosphorylation grants access to distinct activation loop conformations, steering the inactive-to-active conformational transformation. Then we propose the binding mode of CGP57380 to active Mnk2, and evaluate key interactions that could be critical for future Mnk-targeted inhibitors.
  
  
  CONCLUSIONS
  Critical insights of the Mnk2 activation process are gained, while providing a platform for designing Mnk-targeted anticancer agents.
authors: Centre for Drug Discovery & Development, Sansom Institute for Health Research, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide SA 5001, Australia.
authors: Malika
authors: M
authors: Kumarasiri
authors: Theodosia
authors: T
authors: Teo
authors: Shudong
authors: S
authors: Wang
mesh_terms: D055808:Drug Discovery; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases