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| | <StructureSection load='6bqx' size='340' side='right'caption='[[6bqx]], [[Resolution|resolution]] 1.99Å' scene=''> | | <StructureSection load='6bqx' size='340' side='right'caption='[[6bqx]], [[Resolution|resolution]] 1.99Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bqx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BQX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BQX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bqx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BQX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BQX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9AG:N-methyl-1-(4-phenoxyphenyl)methanamine'>9AG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.992Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wf5|4wf5]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9AG:N-methyl-1-(4-phenoxyphenyl)methanamine'>9AG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dsbA, dsf, ppfA, b3860, JW3832 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6bqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bqx OCA], [https://pdbe.org/6bqx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bqx RCSB], [https://www.ebi.ac.uk/pdbsum/6bqx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bqx ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bqx OCA], [http://pdbe.org/6bqx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bqx RCSB], [http://www.ebi.ac.uk/pdbsum/6bqx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bqx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DSBA_ECOLI DSBA_ECOLI]] Required for disulfide bond formation in some periplasmic proteins such as PhoA or OmpA. Acts by transferring its disulfide bond to other proteins and is reduced in the process. DsbA is reoxidized by DsbB. Required for pilus biogenesis. PhoP-regulated transcription is redox-sensitive, being activated when the periplasm becomes more reducing (deletion of dsbA/dsbB, treatment with dithiothreitol). MgrB acts between DsbA/DsbB and PhoP/PhoQ in this pathway.<ref>PMID:1429594</ref> <ref>PMID:22267510</ref> | + | [https://www.uniprot.org/uniprot/DSBA_ECOLI DSBA_ECOLI] Required for disulfide bond formation in some periplasmic proteins such as PhoA or OmpA. Acts by transferring its disulfide bond to other proteins and is reduced in the process. DsbA is reoxidized by DsbB. Required for pilus biogenesis. PhoP-regulated transcription is redox-sensitive, being activated when the periplasm becomes more reducing (deletion of dsbA/dsbB, treatment with dithiothreitol). MgrB acts between DsbA/DsbB and PhoP/PhoQ in this pathway.<ref>PMID:1429594</ref> <ref>PMID:22267510</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ecoli]] | + | [[Category: Escherichia coli K-12]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Heras, B]] | + | [[Category: Heras B]] |
| - | [[Category: Paxman, J J]] | + | [[Category: Paxman JJ]] |
| - | [[Category: Scanlon, M J]] | + | [[Category: Scanlon MJ]] |
| - | [[Category: Totsika, M]] | + | [[Category: Totsika M]] |
| - | [[Category: Wang, G]] | + | [[Category: Wang G]] |
| - | [[Category: Disulphide catalyst]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Thiol oxidase]]
| + | |
| - | [[Category: Virulence factor foldase]]
| + | |
| Structural highlights
Function
DSBA_ECOLI Required for disulfide bond formation in some periplasmic proteins such as PhoA or OmpA. Acts by transferring its disulfide bond to other proteins and is reduced in the process. DsbA is reoxidized by DsbB. Required for pilus biogenesis. PhoP-regulated transcription is redox-sensitive, being activated when the periplasm becomes more reducing (deletion of dsbA/dsbB, treatment with dithiothreitol). MgrB acts between DsbA/DsbB and PhoP/PhoQ in this pathway.[1] [2]
Publication Abstract from PubMed
AIMS: DsbA catalyses disulfide bond formation in secreted and outer membrane proteins in bacteria. In pathogens, DsbA is a major facilitator of virulence constituting a target for antivirulence antimicrobial development. However, many pathogens encode multiple and diverse DsbA enzymes for virulence factor folding during infection. The aim of this study was to determine whether our recently identified inhibitors of <i>Escherichia coli </i>K-12 DsbA can inhibit the diverse DsbA enzymes found in two important human pathogens and attenuate their virulence. RESULTS: DsbA inhibitors from two chemical classes (phenylthiophene and phenoxyphenyl derivatives) inhibited the virulence of uropathogenic <i>Escherichia coli</i> (UPEC) and <i>Salmonella enterica</i> serovar Typhimurium, encoding two and three diverse DsbA homologues, respectively. Inhibitors blocked the virulence of <i>dsbA</i> null mutants complemented with structurally diverse DsbL and SrgA, suggesting they were not selective for prototypical DsbA. Structural characterisation of DsbA-inhibitor complexes showed that compounds from each class bind in a similar region of the hydrophobic groove adjacent to the CPHC active site. Modelling of DsbL- and SrgA-inhibitor interactions showed that these accessory enzymes could accommodate the inhibitors in their different hydrophobic grooves, supporting our in vivo findings. Furthermore, we identified highly conserved residues surrounding the active site for 20 diverse bacterial DsbA enzymes, which could be exploited in developing inhibitors with a broad-spectrum of activity. INNOVATION AND CONCLUSION: We have developed tools to analyse the specificity of DsbA inhibitors in bacterial pathogens encoding multiple DsbA enzymes. This work demonstrates that DsbA inhibitors can be developed to target diverse homologues found in bacteria.
INHIBITION OF DIVERSE DsbA ENZYMES IN MULTI-DsbA ENCODING PATHOGENS.,Totsika M, Vagenas D, Paxman JJ, Wang G, Dhouib R, Sharma P, Martin JL, Scanlon MJ, Heras B Antioxid Redox Signal. 2017 Dec 14. doi: 10.1089/ars.2017.7104. PMID:29237285[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Akiyama Y, Kamitani S, Kusukawa N, Ito K. In vitro catalysis of oxidative folding of disulfide-bonded proteins by the Escherichia coli dsbA (ppfA) gene product. J Biol Chem. 1992 Nov 5;267(31):22440-5. PMID:1429594
- ↑ Lippa AM, Goulian M. Perturbation of the oxidizing environment of the periplasm stimulates the PhoQ/PhoP system in Escherichia coli. J Bacteriol. 2012 Mar;194(6):1457-63. doi: 10.1128/JB.06055-11. Epub 2012 Jan 20. PMID:22267510 doi:http://dx.doi.org/10.1128/JB.06055-11
- ↑ Totsika M, Vagenas D, Paxman JJ, Wang G, Dhouib R, Sharma P, Martin JL, Scanlon MJ, Heras B. INHIBITION OF DIVERSE DsbA ENZYMES IN MULTI-DsbA ENCODING PATHOGENS. Antioxid Redox Signal. 2017 Dec 14. doi: 10.1089/ars.2017.7104. PMID:29237285 doi:http://dx.doi.org/10.1089/ars.2017.7104
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