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Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.

Dinér P, Veide Vilg J, Kjellén J, Migdal I, Andersson T, Gebbia M, Giaever G, Nislow C, Hohmann S, Wysocki R, Tamás MJ, Grøtli M - PLoS ONE (2011)

Bottom Line: These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo.Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress.Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Chemistry, University of Gothenburg, Göteborg, Sweden.

ABSTRACT
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

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The ATP binding site of Hog1.A) Schematic picture of the ATP binding site of Hog1 from homology                            modeling using p38α (1a9u) as the template. B) Docking of                            triazole-based inhibitors 4a–e (yellow)                            together with SB203580 (blue) into the ATP-binding site of                            Hog1.
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pone-0020012-g002: The ATP binding site of Hog1.A) Schematic picture of the ATP binding site of Hog1 from homology modeling using p38α (1a9u) as the template. B) Docking of triazole-based inhibitors 4a–e (yellow) together with SB203580 (blue) into the ATP-binding site of Hog1.

Mentions: A new series of 4- and 5-substituted 1,2,3-triazoles (compounds 4a–e) were designed to have amine functionality in the 2-position of the pyridine ring that could potentially form an extra hydrogen bond with the hinge region (Figure 2A). The new triazole compounds 4a–e were docked into the homology model of Hog1 [28], [29]. The binding mode of the amine-containing triazoles (yellow) is similar to the binding mode of the SB203580 inhibitor (a known inhibitor of p38α, p38β, and AKT/PKB; in blue); i.e., the 4-flourophenyl group interacts with hydrophobic region I and the nitrogen in the pyridine group hydrogen bonds to the amide of Gln103 in the hinge region (Figure 2B).


Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.

Dinér P, Veide Vilg J, Kjellén J, Migdal I, Andersson T, Gebbia M, Giaever G, Nislow C, Hohmann S, Wysocki R, Tamás MJ, Grøtli M - PLoS ONE (2011)

The ATP binding site of Hog1.A) Schematic picture of the ATP binding site of Hog1 from homology                            modeling using p38α (1a9u) as the template. B) Docking of                            triazole-based inhibitors 4a–e (yellow)                            together with SB203580 (blue) into the ATP-binding site of                            Hog1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104989&req=5

pone-0020012-g002: The ATP binding site of Hog1.A) Schematic picture of the ATP binding site of Hog1 from homology modeling using p38α (1a9u) as the template. B) Docking of triazole-based inhibitors 4a–e (yellow) together with SB203580 (blue) into the ATP-binding site of Hog1.
Mentions: A new series of 4- and 5-substituted 1,2,3-triazoles (compounds 4a–e) were designed to have amine functionality in the 2-position of the pyridine ring that could potentially form an extra hydrogen bond with the hinge region (Figure 2A). The new triazole compounds 4a–e were docked into the homology model of Hog1 [28], [29]. The binding mode of the amine-containing triazoles (yellow) is similar to the binding mode of the SB203580 inhibitor (a known inhibitor of p38α, p38β, and AKT/PKB; in blue); i.e., the 4-flourophenyl group interacts with hydrophobic region I and the nitrogen in the pyridine group hydrogen bonds to the amide of Gln103 in the hinge region (Figure 2B).

Bottom Line: These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo.Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress.Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Chemistry, University of Gothenburg, Göteborg, Sweden.

ABSTRACT
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

Show MeSH
Related in: MedlinePlus