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3r5p

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Revision as of 08:13, 6 December 2023

Structure of Ddn, the Deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824

Structural highlights

3r5p is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DDN_MYCTU Nitroreductase involved in the bioreductive activation of the antitubercular prodrug PA-824 (nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It converts PA-824 into three primary metabolites; the major one is the des-nitroimidazole (des-nitro) which generated reactive nitrogen species, including nitric oxide (NO). Reactive nitrogen species play a major role in mammalian defense against mycobacterial infections.^[1] ^[2]

Publication Abstract from PubMed

Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F(420) deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F(420) and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data.

Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824.,Cellitti SE, Shaffer J, Jones DH, Mukherjee T, Gurumurthy M, Bursulaya B, Boshoff HI, Choi I, Nayyar A, Lee YS, Cherian J, Niyomrattanakit P, Dick T, Manjunatha UH, Barry CE 3rd, Spraggon G, Geierstanger BH Structure. 2012 Jan 11;20(1):101-12. PMID:22244759^[3]

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

References

↑ Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, Daniels L, Dick T, Pang SS, Barry CE 3rd. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):431-6. Epub 2005 Dec 30. PMID:16387854 doi:http://dx.doi.org/10.1073/pnas.0508392103
↑ Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE 3rd. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008 Nov 28;322(5906):1392-5. doi: 10.1126/science.1164571. PMID:19039139 doi:http://dx.doi.org/10.1126/science.1164571
↑ Cellitti SE, Shaffer J, Jones DH, Mukherjee T, Gurumurthy M, Bursulaya B, Boshoff HI, Choi I, Nayyar A, Lee YS, Cherian J, Niyomrattanakit P, Dick T, Manjunatha UH, Barry CE 3rd, Spraggon G, Geierstanger BH. Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824. Structure. 2012 Jan 11;20(1):101-12. PMID:22244759 doi:10.1016/j.str.2011.11.001

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3r5p"

@@ Line 3: / Line 3: @@
 <StructureSection load='3r5p' size='340' side='right'caption='[[3r5p]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3r5p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R5P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3r5p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R5P FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
-<tr id='NonStdRes'><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=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3r5l|3r5l]], [[3r5r|3r5r]], [[3r5w|3r5w]], [[3r5y|3r5y]], [[3r5z|3r5z]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ddn, MT3651, Rv3547 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=3r5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r5p OCA], [https://pdbe.org/3r5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r5p RCSB], [https://www.ebi.ac.uk/pdbsum/3r5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r5p ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/DDN_MYCTU DDN_MYCTU]] Nitroreductase involved in the bioreductive activation of the antitubercular prodrug PA-824 (nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It converts PA-824 into three primary metabolites; the major one is the des-nitroimidazole (des-nitro) which generated reactive nitrogen species, including nitric oxide (NO). Reactive nitrogen species play a major role in mammalian defense against mycobacterial infections.<ref>PMID:16387854</ref> <ref>PMID:19039139</ref>
+[https://www.uniprot.org/uniprot/DDN_MYCTU DDN_MYCTU] Nitroreductase involved in the bioreductive activation of the antitubercular prodrug PA-824 (nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It converts PA-824 into three primary metabolites; the major one is the des-nitroimidazole (des-nitro) which generated reactive nitrogen species, including nitric oxide (NO). Reactive nitrogen species play a major role in mammalian defense against mycobacterial infections.<ref>PMID:16387854</ref> <ref>PMID:19039139</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 21: @@
 ==See Also==
-*[[Nitroreductase|Nitroreductase]]
+*[[Nitroreductase 3D structures|Nitroreductase 3D structures]]
 == References ==
 <references/>
@@ Line 29: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Barry, C E]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Boshoff, H I.M]]
+[[Category: Barry CE]]
-[[Category: Bursulaya, B]]
+[[Category: Boshoff HIM]]
-[[Category: Cellitti, S E]]
+[[Category: Bursulaya B]]
-[[Category: Cherian, J]]
+[[Category: Cellitti SE]]
-[[Category: Choi, I]]
+[[Category: Cherian J]]
-[[Category: Dick, T]]
+[[Category: Choi I]]
-[[Category: Geierstanger, B H]]
+[[Category: Dick T]]
-[[Category: Gurumurthy, M]]
+[[Category: Geierstanger BH]]
-[[Category: Jones, D H]]
+[[Category: Gurumurthy M]]
-[[Category: Lee, Y S]]
+[[Category: Jones DH]]
-[[Category: Manjunatha, U H]]
+[[Category: Lee YS]]
-[[Category: Mukherjee, T]]
+[[Category: Manjunatha UH]]
-[[Category: Nayya, A]]
+[[Category: Mukherjee T]]
-[[Category: Niyomrattanakit, P]]
+[[Category: Nayya A]]
-[[Category: Shaffer, J]]
+[[Category: Niyomrattanakit P]]
-[[Category: Spraggon, G]]
+[[Category: Shaffer J]]
-[[Category: Deazaflavin-dependent nitroreductase]]
+[[Category: Spraggon G]]
-[[Category: Duf385]]
-[[Category: Nitroimidazole]]
-[[Category: Oxidoreductase]]
-[[Category: Pa-824]]
-[[Category: Split barrel-like fold]]

3r5p

From Proteopedia

Revision as of 08:13, 6 December 2023

Structure of Ddn, the Deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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