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Structure-based des...
Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
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- Kulén, Martina (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Lindgren, Marie (author)
- Umeå universitet,Klinisk bakteriologi,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS)
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- Hansen, Sabine (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR)
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- Cairns, Andrew G. (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Grundström, Christin (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Begum, Afshan (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- van der Lingen, Ingeborg (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Brännström, Kristoffer (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Hall, Michael, 1980- (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Sauer, Uwe H. (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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- Johansson, Jörgen (author)
- Umeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Sauer-Eriksson, A. Elisabeth (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Molekylär Infektionsmedicin, Sverige (MIMS)
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- Almqvist, Fredrik (author)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Molekylär Infektionsmedicin, Sverige (MIMS)
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(creator_code:org_t)
- 2018-04-18
- 2018
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:9, s. 4165-4175
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Kulén, Martina
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Lindgren, Marie
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Hansen, Sabine
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Cairns, Andrew G ...
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Grundström, Chri ...
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Begum, Afshan
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van der Lingen, ...
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Brännström, Kris ...
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Hall, Michael, 1 ...
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Sauer, Uwe H.
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Johansson, Jörge ...
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Sauer-Eriksson, ...
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Almqvist, Fredri ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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Journal of Medic ...
- By the university
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Umeå University