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==NpsA-ThdA, an artificially fused Adenylation-PCP di-domain NRPS from Klebsiella oxytoca==
<StructureSection load='6vhy' size='340' side='right'caption='[[6vhy]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</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'>[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>
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== 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<ref>PMID:32485104</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vhy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Gulick AM]]
[[Category: Kreitler DF]]