View source for 7t33


==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==
<StructureSection load='7t33' size='340' side='right'caption='[[7t33]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7t33]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_influenzae_Rd_KW20 Haemophilus influenzae Rd KW20]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 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]] 2.301&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NIO:NICOTINIC+ACID'>NIO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Y1278_HAEIN Y1278_HAEIN] 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:35441146</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7t33" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Haemophilus influenzae Rd KW20]]
[[Category: Large Structures]]
[[Category: Bruner SD]]
[[Category: Wanniarachchi TN]]