View source for 2wzw


==Crystal structure of the FMN-dependent nitroreductase NfnB from Mycobacterium smegmatis in complex with NADPH==
<StructureSection load='2wzw' size='340' side='right'caption='[[2wzw]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2wzw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WZW 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]] 1.8&#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=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=2wzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wzw OCA], [https://pdbe.org/2wzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wzw RCSB], [https://www.ebi.ac.uk/pdbsum/2wzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wzw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NFNB_MYCS2 NFNB_MYCS2] Confers resistance to antitubercular drugs benzothiazinone (BTZ) and dinitrobenzamide (DNB). Inactivates BTZ and DNB by reducing an essential nitro group of these compounds to amino group or to hydroxyl amine, respectively, using NADH or NADPH as source of reducing equivalents; two electrons are transferred (PubMed:22069462, PubMed:20624223). Able to reduce the nitro group of bicyclic nitroimidazole PA-824, but not of quinone menadione, nitrofurazone, methyl-4-nitrobenzoate, 4-nitrobenzene methyl sulfonate or 4-nitroacetophenone (PubMed:20624223).<ref>PMID:20624223</ref> <ref>PMID:22069462</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wz/2wzw_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2wzw ConSurf].
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== Publication Abstract from PubMed ==
Summary Tuberculosis is still a leading cause of death in developing countries, for which there is an urgent need for new pharmacological agents. The synthesis of the novel antimycobacterial drug class of benzothiazinones (BTZs) and the identification of their cellular target as DprE1 (Rv3790), a component of the decaprenylphosphoryl-beta-d-ribose 2'-epimerase complex, have been reported recently. Here, we describe the identification and characterization of a novel resistance mechanism to BTZ in Mycobacterium smegmatis. The overexpression of the nitroreductase NfnB leads to the inactivation of the drug by reduction of a critical nitro-group to an amino-group. The direct involvement of NfnB in the inactivation of the lead compound BTZ043 was demonstrated by enzymology, microbiological assays and gene knockout experiments. We also report the crystal structure of NfnB in complex with the essential cofactor flavin mononucleotide, and show that a common amino acid stretch between NfnB and DprE1 is likely to be essential for the interaction with BTZ. We performed docking analysis of NfnB-BTZ in order to understand their interaction and the mechanism of nitroreduction. Although Mycobacterium tuberculosis seems to lack nitroreductases able to inactivate these drugs, our findings are valuable for the design of new BTZ molecules, which may be more effective in vivo.

Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance.,Manina G, Bellinzoni M, Pasca MR, Neres J, Milano A, de Jesus Lopes Ribeiro AL, Buroni S, Skovierova H, Dianiskova P, Mikusova K, Marak J, Makarov V, Giganti D, Haouz A, Lucarelli AP, Degiacomi G, Piazza A, Chiarelli LR, De Rossi E, Salina E, Cole ST, Alzari PM, Riccardi G Mol Microbiol. 2010 Jul 6. PMID:20624223<ref>PMID:20624223</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Nitroreductase 3D structures|Nitroreductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycolicibacterium smegmatis MC2 155]]
[[Category: Alzari PM]]
[[Category: Bellinzoni M]]
[[Category: Manina G]]
[[Category: Riccardi G]]