The With-No-Lysine (WNK) kinase is considered to be a master regulator for various cation-chloride cotransporters involved in maintaining cell-volume and ion homeostasis. Here, we have investigated the phosphorylation-induced structural dynamics of the WNK1 kinase bound to an inhibitor via atomistic molecular dynamics simulations. Results from our simulations show that the phosphorylation at Ser382 could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg264 and Glu268 in the unphosphorylated system is disengaged after the phosphorylation, and Glu268 reorients itself and forms a stable salt-bridge with Arg348. The dynamic cross-correlation analysis shows that phosphorylation diminishes anticorrelated motions and increases correlated motions between different domains. Structural network analysis reveals that the phosphorylation causes structural rearrangements and shortens the communication path between the αC-helix and catalytic loop, making the binding pocket more suitable for accommodating the ligand. Overall, we have characterized the structural changes in the WNK kinase because of phosphorylation in the A-loop, which might help in designing rational drugs.
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