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Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations

[Image: see text] 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 inhib...

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Autores principales: Jonniya, Nisha Amarnath, Sk, Md Fulbabu, Kar, Parimal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812135/
https://www.ncbi.nlm.nih.gov/pubmed/31656913
http://dx.doi.org/10.1021/acsomega.9b02187
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author Jonniya, Nisha Amarnath
Sk, Md Fulbabu
Kar, Parimal
author_facet Jonniya, Nisha Amarnath
Sk, Md Fulbabu
Kar, Parimal
author_sort Jonniya, Nisha Amarnath
collection PubMed
description [Image: see text] 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(382) could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg(264) and Glu(268) in the unphosphorylated system is disengaged after the phosphorylation, and Glu(268) reorients itself and forms a stable salt-bridge with Arg(348). 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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spelling pubmed-68121352019-10-25 Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations Jonniya, Nisha Amarnath Sk, Md Fulbabu Kar, Parimal ACS Omega [Image: see text] 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(382) could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg(264) and Glu(268) in the unphosphorylated system is disengaged after the phosphorylation, and Glu(268) reorients itself and forms a stable salt-bridge with Arg(348). 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. American Chemical Society 2019-10-11 /pmc/articles/PMC6812135/ /pubmed/31656913 http://dx.doi.org/10.1021/acsomega.9b02187 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Jonniya, Nisha Amarnath
Sk, Md Fulbabu
Kar, Parimal
Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title_full Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title_fullStr Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title_full_unstemmed Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title_short Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations
title_sort investigating phosphorylation-induced conformational changes in wnk1 kinase by molecular dynamics simulations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812135/
https://www.ncbi.nlm.nih.gov/pubmed/31656913
http://dx.doi.org/10.1021/acsomega.9b02187
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