Crystal structure of the kinase domain of serum and glucocorticoid-regulated kinase 1 in complex with AMP PNP
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Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine protein kinase of the AGC family which participates in the control of epithelial ion transport and is implicated in proliferation and apoptosis. We report here the 1.9 A crystal structure of the catalytic domain of inactive human SGK1 in complex with AMP-PNP. SGK1 exists as a dimer formed by two intermolecular disulfide bonds between Cys258 in the activation loop and Cys193. Although most of the SGK1 structure closely resembles the common protein kinase fold, the structure around the active site is unique when compared to most protein kinases. The alphaC helix is not present in this inactive form of SGK1 crystal structure; instead, the segment corresponding to the C helix forms a beta-strand that is stabilized by the N-terminal segment of the activation loop through a short antiparallel beta-sheet. Since the differences from other kinases occur around the ATP binding site, this structure can provide valuable insight into the design of selective and highly potent ATP-competitive inhibitors of SGK1 kinase.
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In the inactive form of SGK1, the αC helix typical in other structures is absent, and the segment corresponding to the C helix forms a β-strand stabilized by a short anti-parallel β-sheet from the N-terminal segment of the activation loop.
“In the inactive form of SGK1, the αC helix typical in other structures is absent. Instead, the segment corresponding to the C helix forms a β-strand. This strand is stabilized by a short anti-parallel β-sheet from the N-terminal segment of the activation loop”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Zhao et al., 2007
The human SGK1 gene is located on chromosome 6 at 6q23, spans 148,867 bases, contains 14 coding exons, and encodes a 431-amino-acid protein of approximately 49 kDa.
“The SGK1 gene in the human genome is located on chromosome 6 at the 6q23 region, spans 148,867 bases, and contains 14 coding exons. It encodes the SGK1 protein, which comprises 431 amino acids and has a molecular mass of approximately 49 kDa”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Zhao et al., 2007
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Frödin, M., Antal, T. L., Dümmler, B. A., Jensen, C. J., Deak, M., Gammeltoft, S., & Biondi, R. M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf551 · Cited by 275 · see citing works
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
Computational insights into the active structure of SGK1 and its implication for ligand design
Akhoon, B. A., Gandhi, N. S., & Pandey, R. (2019) · Biochimie · doi:10.1016/j.biochi.2019.07.007 · Cited by 9 · see citing works
- Authors
- Zhao, B., Lehr, R., Smallwood, A. M., Ho, T. F., Maley, K., Randall, T., Head, M. S., Koretke, K. K., & Schnackenberg, C. G.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Zhao, Baoguang
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2007-12
- Volume
- 16
- Issue
- 12
- Pages
- 2761-2769
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2222817
- OpenAlex
- W1987221725
- Cited by
- 54
- References
- 1
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 1
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SGK1, AGC kinase family, αC-helix, ATP binding site, kinase inhibitors
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Adenosine Triphosphate, Adenylyl Imidodiphosphate, Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Molecular Sequence Data, Protein Conformation, Molecular Structure, Sequence Alignment, Protein Serine-Threonine Kinases, Protein Structure, Secondary, Protein Structure, Tertiary, Immediate-Early Proteins, Crystallography, X-Ray, Dimerization, Catalytic Domain, Hydrophobic and Hydrophilic Interactions
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