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Structure-based des...
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Kulén, MartinaUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
(author)
Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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2018-04-18
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American Chemical Society (ACS),2018
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:umu-148830
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-148830URI
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https://doi.org/10.1021/acs.jmedchem.8b00289DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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 and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Lindgren, MarieUmeå universitet,Klinisk bakteriologi,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)maelin02
(author)
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Hansen, SabineUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR)(Swepub:umu)saha0206
(author)
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Cairns, Andrew G.Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)anca0145
(author)
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Grundström, ChristinUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)chgr0001
(author)
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Begum, AfshanUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)afbe0001
(author)
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van der Lingen, IngeborgUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)inva0011
(author)
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Brännström, KristofferUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)krbr0001
(author)
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Hall, Michael,1980-Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)milhll01
(author)
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Sauer, Uwe H.Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)uwsa0001
(author)
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Johansson, JörgenUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)jojo0001
(author)
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Sauer-Eriksson, A. ElisabethUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)elsa0002
(author)
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Almqvist, FredrikUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)fral0001
(author)
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Umeå universitetKemiska institutionen
(creator_code:org_t)
Related titles
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In:Journal of Medicinal Chemistry: American Chemical Society (ACS)61:9, s. 4165-41750022-26231520-4804
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