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Aim: 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. Conclusion: Critical insights of the Mnk2 activation process are gained, while providing a platform for designing Mnk-targeted anticancer agents.