ao9b02187_si_001.pdf (2.09 MB)
Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
journal contribution
posted on 2019-10-11, 09:03 authored by Nisha
Amarnath Jonniya, Md Fulbabu Sk, Parimal KarThe
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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Phosphorylation-Induced Conformational ChangesArg 348Arg 264cross-correlation analysisactivation loopGlu 268 reorientsα C-helixMolecular Dynamics SimulationsGlu 268WNK 1 Kinasesimulations showWNK kinaseSer 382A-loopStructural network analysisphosphorylation causesbinding pocketanticorrelated motionsunphosphorylated systemmaster regulatorcommunication pathcation-chloride cotransportersion homeostasisdynamics simulationsintrahelix salt-bridgeWNK 1 kinase
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