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Exploring the Activ...
Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins.
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- Hering, Jenny (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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- Dunevall, Elin, 1986 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Snijder, Arjan (author)
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Eriksson, Per-Olof (author)
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Jackson, Michael A (author)
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Hartman, Trina M (author)
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Ting, Ran (author)
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Chen, Hongming (author)
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Price, Neil P J (author)
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- Brändén, Gisela, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Ek, Margareta (author)
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(creator_code:org_t)
- 2020-11-09
- 2020
- English.
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In: ACS chemical biology. - : American Chemical Society (ACS). - 1554-8937 .- 1554-8929. ; 15:11, s. 2885-2895
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https://pubs.acs.org...
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https://doi.org/10.1...
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Abstract
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- The alarming growth of antibiotic resistance that is currently ongoing is a serious threat to human health. One of the most promising novel antibiotic targets is MraY (phospho-MurNAc-pentapeptide-transferase), an essential enzyme in bacterial cell wall synthesis. Through recent advances in biochemical research, there is now structural information available for MraY, and for its human homologue GPT (GlcNAc-1-P-transferase), that opens up exciting possibilities for structure-based drug design. The antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through its binding to GPT. In this work, we have used tunicamycin and modified versions of tunicamycin as tool compounds to explore the active site of MraY and to gain further insight into what determines inhibitor potency. We have investigated tunicamycin variants where the following motifs have been modified: the length and branching of the tunicamycin fatty acyl chain, the saturation of the fatty acyl chain, the 6″-hydroxyl group of the GlcNAc ring, and the ring structure of the uracil motif. The compounds are analyzed in terms of how potently they bind to MraY, inhibit the activity of the enzyme, and affect the protein thermal stability. Finally, we rationalize these results in the context of the protein structures of MraY and GPT.
Subject headings
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Hering, Jenny
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Dunevall, Elin, ...
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Snijder, Arjan
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Eriksson, Per-Ol ...
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Jackson, Michael ...
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Hartman, Trina M
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show more...
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Ting, Ran
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Chen, Hongming
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Price, Neil P J
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Brändén, Gisela, ...
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Ek, Margareta
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biophysics
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Structural Biolo ...
- Articles in the publication
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ACS chemical bio ...
- By the university
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University of Gothenburg