2wzw

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the FMN-dependent nitroreductase NfnB from Mycobacterium smegmatis in complex with NADPH

Structural highlights

2wzw is a 2 chain structure with sequence from Mycolicibacterium smegmatis MC2 155. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol. 2010 Jul 6. PMID:20624223 doi:10.1111/j.1365-2958.2010.07277.x
↑ Ribeiro AL, Degiacomi G, Ewann F, Buroni S, Incandela ML, Chiarelli LR, Mori G, Kim J, Contreras-Dominguez M, Park YS, Han SJ, Brodin P, Valentini G, Rizzi M, Riccardi G, Pasca MR. Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. PLoS One. 2011;6(11):e26675. PMID:22069462 doi:10.1371/journal.pone.0026675
↑ 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. Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol. 2010 Jul 6. PMID:20624223 doi:10.1111/j.1365-2958.2010.07277.x

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2wzw"

@@ Line 1: / Line 1: @@
-==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=''>
+==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 [http://en.wikipedia.org/wiki/Mycobacterium_smegmatis Mycobacterium smegmatis]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WZW FirstGlance]. <br>
+<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><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><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><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wzv|2wzv]]</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>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wzw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wzw RCSB], [http://www.ebi.ac.uk/pdbsum/2wzw PDBsum]</span></td></tr>
+</table>
-<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>
+    <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/chain_selection.php?pdb_ID=2ata ConSurf].
+</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].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 26: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2wzw" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Nitroreductase|Nitroreductase]]
+*[[Nitroreductase 3D structures|Nitroreductase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Mycobacterium smegmatis]]
+[[Category: Large Structures]]
-[[Category: Alzari, P M.]]
+[[Category: Mycolicibacterium smegmatis MC2 155]]
-[[Category: Bellinzoni, M.]]
+[[Category: Alzari PM]]
-[[Category: Manina, G.]]
+[[Category: Bellinzoni M]]
-[[Category: Riccardi, G.]]
+[[Category: Manina G]]
-[[Category: Nitroreductase]]
+[[Category: Riccardi G]]
-[[Category: Oxidoreductase]]

2wzw

From Proteopedia

Current revision

Crystal structure of the FMN-dependent nitroreductase NfnB from Mycobacterium smegmatis in complex with NADPH

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox