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Cited by 9Protein Structure and DynamicsProtein Kinase Regulation and GTPase SignalingComputational Drug Discovery Methods

Computational insights into the active structure of SGK1 and its implication for ligand design

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Akhoon, Bashir A., Gandhi, Neha S., Pandey, Rakesh·2019·Biochimie
DOI 10.1016/j.biochi.2019.07.007
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Abstract

Serum- and glucocorticoid-inducible kinase 1 (SGK1), a protein kinase, shares significant structural similarity with other members of the AGC protein kinase family. It has been reported that the inactive SGK1 structure lacks αC helix and this unique feature makes it distinct from other protein kinases. Activation of SGK1 by PDK1 requires phosphorylation at Thr256, but the structural insights of the activation remain unclear. The co-crystal structures of small molecule inhibitors, Magnesium (Mg +2 ) and ATP bound to the inactive SGK1 are reported however the important regulatory domains such as αC helix are missing in these crystal structures. We modelled the missing αC domain and employed computational molecular dynamics simulations to study the conformational changes in the WT and phosphorylated human SGK1 to systematically investigate how the individual domain motions are modulated by the binding of substrate and Mg +2 . The MD results corroborate with the experiential findings and has shown that the inactive SGK1 lacks αC helix content. Surprisingly, we find that the active SGK1 structure closely resembles with other protein kinases and adopt the αC helix content up on SGK1 phosphorylation. However, the residues participating in αC helix formation are fewer than reported in protein kinase A structure, a close relative of SGK1. The computational binding analysis reveals that most of the SGK1 selective inhibitors have less binding affinity for active SGK1 than some FDA-appro…

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  • Activation of SGK1 involves mTORC2 phosphorylating Ser422, followed by PDK1 transferring phosphate to Thr256, which phosphorylates the activation loop and enlarges the ATP-binding site.

    “In the activation process of SGK1, extracellular stimuli induce the activation of mTORC2, which phosphorylates Ser422 on SGK1’s hydrophobic motif (Garcia-Martinez and Alessi, 2008). Subsequently, 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) is recruited to the phosphorylated Ser, leading to the transfer of a phosphate group to Thr256 within the kinase domain of SGK1 (Biondi et al., 2001),”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Akhoon et al., 2019

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Authors
Akhoon, B. A., Gandhi, N. S., & Pandey, R.
Affiliations
  • Central Institute of Medicinal and Aromatic Plants (IN)
  • Queensland University of Technology (AU)
Corresponding author
Pandey, Rakesh
ORCID
Venue
Biochimie
Publisher
Elsevier BV
Published
2019-10
Volume
165
Pages
57-66
ISSN
  • 0037-9042 (ISSN-L)
  • 0300-9084
DOI
10.1016/j.biochi.2019.07.007
OpenAlex
W2960101084
Cited by
9
References
56
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1
FWCI
0.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimie (publishedVersion)
  • PubMed (publishedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by-nc-nd)
Funders
  • CSIR - Indian Institute of Chemical Biology (31/029(0251)/2013-EMR-I)
  • Qingdao Technological University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
SGK1, serum- and glucocorticoid-inducible kinase, protein kinase activation, αC-helix, PDK1, magnesium binding, ATP binding, conformational dynamics, kinase inhibitors, ligand binding affinity, AGC protein kinases, kinase inhibitor design
MeSH terms
Protein Domains, Serum-Glucocorticoid Regulated Kinases, Humans, Ligands, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Catalytic Domain, Molecular Dynamics Simulation

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