6vhw

Klebsiella oxytoca NpsA N-terminal subdomain in complex with 3-hydroxybenzoyl-AMSN

spinqualitylabelsall models 6vhw, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vhw is a 2 chain structure with sequence from Klebsiella oxytoca. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.83Å Ligands: BR, CL, EPE, PEG, PGE, R2V Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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