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| | ==Endoribonuclease in complex with its cognate antitoxin from Mycobacterial species== | | ==Endoribonuclease in complex with its cognate antitoxin from Mycobacterial species== |
| - | <StructureSection load='5xe3' size='340' side='right' caption='[[5xe3]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='5xe3' size='340' side='right'caption='[[5xe3]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5xe3]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XE3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XE3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5xe3]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XE3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XE3 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5xe2|5xe2]]</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]] 2.3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mazF4, mazF-mt7, Rv1495, MTCY277.17 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU]), mazE4, mazE-mt7, Rv1494, MTCY277.16 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=5xe3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xe3 OCA], [https://pdbe.org/5xe3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xe3 RCSB], [https://www.ebi.ac.uk/pdbsum/5xe3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xe3 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xe3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xe3 OCA], [http://pdbe.org/5xe3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xe3 RCSB], [http://www.ebi.ac.uk/pdbsum/5xe3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xe3 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MAZF4_MYCTU MAZF4_MYCTU]] Toxic component of a type II toxin-antitoxin (TA) module. Acts as an endoribonuclease (mRNA interferase) on single-strand mRNA, cleaving between the first and second bases in the sequence UCGCU. Overexpression in M.smegmatis but not E.coli inhibits growth, this effect is neutralized by coexpression with cognate toxin MazE4.<ref>PMID:18485066</ref> Residues 29-56 inhibit ssDNA cleavage by DNA topoisomerase. This fragment does not have mRNA cleavage activity but it inhibits growth upon overexpression in M.smegmatis.<ref>PMID:20724443</ref> [[http://www.uniprot.org/uniprot/MAZE4_MYCTU MAZE4_MYCTU]] Antitoxin component of a type II toxin-antitoxin (TA) module. In M.smegmatis neutralizes the toxic effect of mRNA interferase MazF4, its cognate toxin, on growth.<ref>PMID:20724443</ref> | + | [https://www.uniprot.org/uniprot/MAZF4_MYCTU MAZF4_MYCTU] Toxic component of a type II toxin-antitoxin (TA) module. Acts as an endoribonuclease (mRNA interferase) on single-strand mRNA, cleaving between the first and second bases in the sequence UCGCU. Overexpression in M.smegmatis but not E.coli inhibits growth, this effect is neutralized by coexpression with cognate toxin MazE4.<ref>PMID:18485066</ref> Residues 29-56 inhibit ssDNA cleavage by DNA topoisomerase. This fragment does not have mRNA cleavage activity but it inhibits growth upon overexpression in M.smegmatis.<ref>PMID:20724443</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Myctu]] | + | [[Category: Large Structures]] |
| - | [[Category: Ahn, D H]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Kim, S J]] | + | [[Category: Ahn D-H]] |
| - | [[Category: Lee, B J]] | + | [[Category: Kim S-J]] |
| - | [[Category: Lee, K Y]] | + | [[Category: Lee B-J]] |
| - | [[Category: Lee, S J]] | + | [[Category: Lee K-Y]] |
| - | [[Category: Yoon, H J]] | + | [[Category: Lee SJ]] |
| - | [[Category: Endonuclease]]
| + | [[Category: Yoon HJ]] |
| - | [[Category: Hydrolase-antitoxin complex]]
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| Structural highlights
Function
MAZF4_MYCTU Toxic component of a type II toxin-antitoxin (TA) module. Acts as an endoribonuclease (mRNA interferase) on single-strand mRNA, cleaving between the first and second bases in the sequence UCGCU. Overexpression in M.smegmatis but not E.coli inhibits growth, this effect is neutralized by coexpression with cognate toxin MazE4.[1] Residues 29-56 inhibit ssDNA cleavage by DNA topoisomerase. This fragment does not have mRNA cleavage activity but it inhibits growth upon overexpression in M.smegmatis.[2]
Publication Abstract from PubMed
The bacterial toxin-antitoxin MazEF system in the tuberculosis (TB)-causing bacterium Mycobacterium tuberculosis is activated under unfavorable conditions, including starvation, antibiotic exposure, and oxidative stress. This system contains the ribonucleolytic enzyme MazF and has emerged as a promising drug target for TB treatments targeting the latent stage of M. tuberculosis infection and reportedly mediates a cell death process via a peptide called extracellular death factor (EDF). Although it is well established that the increase in EDFmediated toxicity of MazF drives a cell-killing phenomenon, the molecular details are poorly understood. Moreover, the divergence in sequences among reported EDFs suggests that each bacterial species has a unique EDF. To address these open questions, we report here the structures of MazF4 and MazEF4 complexes from M. tuberculosis, representing the first MazEF structures from this organism. We found that MazF4 possesses a negatively charged MazE4-binding pocket in contrast to the positively charged MazE-binding pockets in homologous MazEF complex structures from other bacteria. Moreover, using NMR spectroscopy and biochemical assays, we unraveled the molecular interactions of MazF4 with its RNA substrate and with a new EDF homolog originating from M. tuberculosis The EDF homolog discovered here possesses a positively charged residue at the C-terminus, making this EDF distinct from previously reported EDFs. Overall, our results suggest that M. tuberculosis evolved a unique MazF and EDF and that the distinctive EDF sequence could serve as a starting point for designing new anti-tuberculosis drugs. We therefore conclude that this study might contribute to the development of a new line of anti-tuberculosis agents.
Structural analyses of the MazEF4 toxin-antitoxin pair in Mycobacterium tuberculosis provide evidence for a unique extracellular death factor.,Ahn DH, Lee KY, Lee SJ, Park SJ, Yoon HJ, Kim SJ, Lee BJ J Biol Chem. 2017 Oct 2. pii: M117.807974. doi: 10.1074/jbc.M117.807974. PMID:28972145[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhu L, Phadtare S, Nariya H, Ouyang M, Husson RN, Inouye M. The mRNA interferases, MazF-mt3 and MazF-mt7 from Mycobacterium tuberculosis target unique pentad sequences in single-stranded RNA. Mol Microbiol. 2008 Aug;69(3):559-69. doi: 10.1111/j.1365-2958.2008.06284.x. Epub, 2008 Jun 28. PMID:18485066 doi:http://dx.doi.org/10.1111/j.1365-2958.2008.06284.x
- ↑ Huang F, He ZG. Characterization of an interplay between a Mycobacterium tuberculosis MazF homolog, Rv1495 and its sole DNA topoisomerase I. Nucleic Acids Res. 2010 Dec;38(22):8219-30. doi: 10.1093/nar/gkq737. Epub 2010, Aug 19. PMID:20724443 doi:http://dx.doi.org/10.1093/nar/gkq737
- ↑ Ahn DH, Lee KY, Lee SJ, Park SJ, Yoon HJ, Kim SJ, Lee BJ. Structural analyses of the MazEF4 toxin-antitoxin pair in Mycobacterium tuberculosis provide evidence for a unique extracellular death factor. J Biol Chem. 2017 Oct 2. pii: M117.807974. doi: 10.1074/jbc.M117.807974. PMID:28972145 doi:http://dx.doi.org/10.1074/jbc.M117.807974
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