Structure Prediction of SPAK C-terminal Domain and Analysis of its Binding to RFXV/I Motifs by Homology Modelling, Docking and Molecular Dynamics Simulation Studies
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Published:2021-11-18
Issue:5
Volume:17
Page:666-675
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ISSN:1573-4099
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Container-title:Current Computer-Aided Drug Design
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language:en
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Short-container-title:CAD
Author:
Alamri Mubarak A.1ORCID,
Alafnan Ahmed D.2,
Afzal Obaid1ORCID,
Alabbas Alhumaidi B.1,
Alqahtani Safar M.1
Affiliation:
1. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj- 11942, Saudi Arabia
2. Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Saudi Arabia
Abstract
Background:
The STE20/SPS1-related proline/alanine-rich kinase (SPAK) is a component
of WNK-SPAK/OSR1 signaling pathway that plays an essential role in blood pressure regulation.
The function of SPAK is mediated by its highly conserved C-terminal domain (CTD) that interacts
with RFXV/I motifs of upstream activators, WNK kinases, and downstream substrate, cation-
chloride cotransporters.
Objective:
To determine and validate the three-dimensional structure of the CTD of SPAK and to study and analyze its
interaction with the RFXV/I motifs.
Methods:
A homology model of SPAK CTD was generated and validated through multiple approaches.
The model was based on utilizing the OSR1 protein kinase as a template. This model was
subjected to a 100 ns molecular dynamic (MD) simulation to evaluate its dynamic stability. The final
equilibrated model was used to dock the RFQV-peptide derived from WNK4 into the primary
pocket that was determined based on the homology sequence between human SPAK and OSR1
CTDs. The mechanism of interaction, conformational rearrangement and dynamic stability of the
binding of RFQV-peptide to SPAK CTD were characterized by molecular docking and molecular
dynamic simulation.
Results:
The MD simulation suggested that the binding of RFQV induces a large conformational
change due to the distribution of salt bridge within the loop regions. These results may help in understanding
the relationship between the structure and function of SPAK CTD and to support the
drug design of potential SPAK kinase inhibitors as antihypertensive agents.
Conclusion:
This study provides deep insight into SPAK CTD structure and function relationship.
Funder
Deanship of Scientific Research (DSR), Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Molecular Medicine,General Medicine