7t33 | pdb_00007t33

The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid

spinqualitylabelsall models 7t33, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7t33 is a 2 chain structure with sequence from Haemophilus influenzae Rd KW20. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.301Å Ligands: FMN, NIO, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Y1278_HAEIN Publication Abstract from PubMed Nitroheterocycle antibiotics, particularly 5-nitroimidazoles, are frequently used for treating anaerobic infections. The antimicrobial activities of these drugs heavily rely on the in vivo bioactivation, mainly mediated by widely distributed bacterial nitroreductases (NTRs). However, the bioactivation can also lead to severe toxicities and drug resistance. Mechanistic understanding of NTR-mediated 5-nitroimidazole metabolism can potentially aid addressing these issues. Here, we report the metabolism of structurally diverse nitroimidazole drug molecules by a NTR from a human pathogen Haemophilus influenzae (HiNfsB). Our detailed bioinformatic analysis uncovered that HiNfsB represents a group of unexplored oxygen-insensitive NTRs. Biochemical characterization of the recombinant enzyme revealed that HiNfsB effectively metabolizes ten clinically used nitroimidazoles. Furthermore, HiNfsB generated not only canonical nitroreduction metabolites but also stable, novel dimeric products from three nitroimidazoles, whose structures were proposed based on the results of high resolution MS and tandem MS analysis. X-ray structural analysis of the enzyme coupled with site-directed mutagenesis identified four active site residues important to its catalysis and broad substrate scope. Finally, transient expression of HiNfsB sensitized an E. coli mutant strain to 5-nitroimidazoles under anaerobic conditions. Together, these results advance our understanding of the metabolism of nitroimidazole antibiotics mediated by a new NTR group and reinforce the research on the natural antibiotic resistome for addressing the antibiotic resistance crisis. Biochemical and structural characterization of Haemophilus influenzae nitroreductase in metabolizing nitroimidazoles.,Liu D, Wanniarachchi TN, Jiang G, Seabra G, Cao S, Bruner SD, Ding Y RSC Chem Biol. 2022 Feb 16;3(4):436-446. doi: 10.1039/d1cb00238d. eCollection, 2022 Apr 6. PMID:35441146 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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