Investigating Phosphorylation-Induced
Conformational Changes in WNK1 Kinase by Molecular
Dynamics Simulations
Nisha
Amarnath Jonniya
Md Fulbabu Sk
Parimal Kar
10.1021/acsomega.9b02187.s001
https://acs.figshare.com/articles/journal_contribution/Investigating_Phosphorylation-Induced_Conformational_Changes_in_WNK1_Kinase_by_Molecular_Dynamics_Simulations/9970190
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 Ser<sup>382</sup> could stabilize the
otherwise flexible activation loop (A-loop). The intrahelix salt-bridge
formed between Arg<sup>264</sup> and Glu<sup>268</sup> in the unphosphorylated
system is disengaged after the phosphorylation, and Glu<sup>268</sup> reorients itself and forms a stable salt-bridge with Arg<sup>348</sup>. 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.
2019-10-11 09:03:20
Phosphorylation-Induced Conformational Changes
Arg 348
Arg 264
cross-correlation analysis
activation loop
Glu 268 reorients
α C-helix
Molecular Dynamics Simulations
Glu 268
WNK 1 Kinase
simulations show
WNK kinase
Ser 382
A-loop
Structural network analysis
phosphorylation causes
binding pocket
anticorrelated motions
unphosphorylated system
master regulator
communication path
cation-chloride cotransporters
ion homeostasis
dynamics simulations
intrahelix salt-bridge
WNK 1 kinase