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Mouse 11?-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

ABSTRACT: Mouse (m) 11?-hydroxysteroid dehydrogenase type 2 (11?HSD2) was homology-modeled, and its structure and ligand-receptor interaction were analyzed. The modeled m11?HSD2 showed significant 3D similarities to the human (h) 11?HSD1 and 2 structures. The contact energy profiles of the m11?HSD2 model were in good agreement with those of the h11?HSD1 and 2 structures. The secondary structure of the m11?HSD2 model exhibited a central 6-stranded all-parallel ?-sheet sandwich-like structure, flanked on both sides by 3-helices. Ramachandran plots revealed that only 1.1% of the amino acid residues were in the disfavored region for m11?HSD2. Further, the molecular surfaces and electrostatic analyses of the m11?HSD2 model at the ligand-binding site exhibited that the model was almost identical to the h11?HSD2 model. Furthermore, docking simulation and ligand-receptor interaction analyses revealed the similarity of the ligand-receptor bound conformation between the m11?HSD2 and h11?HSD2 models. These results indicate that the m11?HSD2 model was successfully evaluated and analyzed. To the best of our knowledge, this is the first report of a m11?HSD2 model with detailed analyses, and our data verify that the mouse model can be utilized for application to the human model to target 11?HSD2 for the development of anticancer drugs.

SUBMITTER: Yamaguchi H

PROVIDER: S-EPMC3236009 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Mouse 11β-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

Yamaguchi Hideaki H Akitaya Tatsuo T Kidachi Yumi Y Kamiie Katsuyoshi K Noshita Toshiro T Umetsu Hironori H Ryoyama Kazuo K

Cancer informatics 20111201

Mouse (m) 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) was homology-modeled, and its structure and ligand-receptor interaction were analyzed. The modeled m11βHSD2 showed significant 3D similarities to the human (h) 11βHSD1 and 2 structures. The contact energy profiles of the m11βHSD2 model were in good agreement with those of the h11βHSD1 and 2 structures. The secondary structure of the m11βHSD2 model exhibited a central 6-stranded all-parallel β-sheet sandwich-like structure, flanked on bo ...[more]

PMID: 22174566

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Dataset Information

Mouse 11?-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

Publications

Mouse 11β-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

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