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| | <StructureSection load='6vhy' size='340' side='right'caption='[[6vhy]], [[Resolution|resolution]] 3.00Å' scene=''> | | <StructureSection load='6vhy' size='340' side='right'caption='[[6vhy]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vhy]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_oxytocus_perniciosus"_flugge_1886 "bacillus oxytocus perniciosus" flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VHY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VHY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vhy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_oxytoca Klebsiella oxytoca]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VHY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QXD:5-deoxy-5-({[(2R)-2-{[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl]sulfanyl}-2-(3-hydroxyphenyl)ethyl]sulfonyl}amino)adenosine'>QXD</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]] 3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AGF18_11090 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=571 "Bacillus oxytocus perniciosus" Flugge 1886])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QXD:5-deoxy-5-({[(2R)-2-{[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl]sulfanyl}-2-(3-hydroxyphenyl)ethyl]sulfonyl}amino)adenosine'>QXD</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vhy OCA], [http://pdbe.org/6vhy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vhy RCSB], [http://www.ebi.ac.uk/pdbsum/6vhy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vhy ProSAT]</span></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=6vhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vhy OCA], [https://pdbe.org/6vhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vhy RCSB], [https://www.ebi.ac.uk/pdbsum/6vhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vhy ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus oxytocus perniciosus flugge 1886]] | + | [[Category: Klebsiella oxytoca]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gulick, A M]] | + | [[Category: Gulick AM]] |
| - | [[Category: Kreitler, D F]] | + | [[Category: Kreitler DF]] |
| - | [[Category: Adenylation]]
| + | |
| - | [[Category: Biosynthetic protein]]
| + | |
| - | [[Category: Nonribosomal peptide synthetase]]
| + | |
| - | [[Category: Nrp]]
| + | |
| - | [[Category: Tilimycin]]
| + | |
| - | [[Category: Tilivalline]]
| + | |
| Structural highlights
Publication Abstract from PubMed
Tilimycin is an enterotoxin produced by the opportunistic pathogen Klebsiella oxytoca that causes antibiotic-associated hemorrhagic colitis (AAHC). This pyrrolobenzodiazepine (PBD) natural product is synthesized by a bimodular nonribosomal peptide synthetase (NRPS) pathway composed of three proteins: NpsA, ThdA, and NpsB. We describe the functional and structural characterization of the fully reconstituted NRPS system and report the steady-state kinetic analysis of all natural substrates and cofactors as well as the structural characterization of both NpsA and ThdA. The mechanism of action of tilimycin was confirmed using DNA adductomics techniques through the detection of putative N-2 guanine alkylation after tilimycin exposure to eukaryotic cells, providing the first structural characterization of a PBD-DNA adduct formed in cells. Finally, we report the rational design of small-molecule inhibitors that block tilimycin biosynthesis in whole cell K. oxytoca (IC50 = 29 +/- 4 muM) through the inhibition of NpsA (KD = 29 +/- 4 nM).
Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen Klebsiella oxytoca.,Alexander EM, Kreitler DF, Guidolin V, Hurben AK, Drake E, Villalta PW, Balbo S, Gulick AM, Aldrich CC ACS Infect Dis. 2020 Jun 24. doi: 10.1021/acsinfecdis.0c00326. PMID:32485104[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Alexander EM, Kreitler DF, Guidolin V, Hurben AK, Drake E, Villalta PW, Balbo S, Gulick AM, Aldrich CC. Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen Klebsiella oxytoca. ACS Infect Dis. 2020 Jun 24. doi: 10.1021/acsinfecdis.0c00326. PMID:32485104 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00326
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